Carole Jalaber

Thibaut Lapotre

Thibaud Morcet-Delattre

Félix Ribet

Stéphane Jouneau

Mathieu Lederlin
email: mathieu.lederlin@chu-rennes.fr

Chest CT in COVID-19 pneumonia: a review of current knowledge

Keywords: COVID-19, Tomography, X-ray computed, Severe acute respiratory syndrome coronavirus 2, Pulmonary embolism AI: artificial intelligence ARDS: acute respiratory distress syndrome COVID-19: coronavirus disease 2019 CT: computed tomography RT-PCR: reverse Transcriptase polymerase chain reaction SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

The current COVID-19 pandemic has highlighted the essential role of chest computed tomography (CT) examination in patient triage in the emergency departments, allowing them to be referred to "COVID" or "non-COVID" wards. Initial chest CT examination must be performed without intravenous administration of iodinated contrast material, but contrast material administration is required when pulmonary embolism is suspected, which seems to be frequent in severe forms of the disease. Typical CT features consist of bilateral groundglass opacities with peripheral, posterior and basal predominance. Lung disease extent on CT correlates with clinical severity. Artificial intelligence could assist radiologists for diagnosis and prognosis evaluation.

Introduction

By June 8, 2020, the COVID-19 pandemic had affected more than 6.9 million people worldwide, resulting in 401,970 deaths (1). The most typical clinical presentation of COVID-19 is an acute febrile respiratory infection with dry cough, dyspnea, fatigue and myalgia.

Approximately 15-20% of patients have severe disease and the mortality is around 2-3% [START_REF] Wu | Characteristics of and Important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention[END_REF][START_REF] Guan | Clinical characteristics of coronavirus disease 2019 in China[END_REF][START_REF] Huang | Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[END_REF].

In the absence of vaccine or specific therapy available to date, it is essential to be able to diagnose this disease as early as possible in order to isolate infected subjects and thus limit the spread of the disease. The method of reference is laboratory testing of nasopharyngeal aspirates for identification of SARS-CoV-2 by reverse transcriptase -polymerase chain reaction (RT-PCR). However, it takes several hours to obtain the results, and the sensitivity of the test is only 60 to 70%, depending on the quality of the sample and the rate of viral replication in the upper respiratory tract [START_REF] Ai | Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases[END_REF][START_REF] Fang | Sensitivity of chest CT for COVID-19: comparison to RT-PCR[END_REF].

Chest computed tomography (CT) has rapidly emerged as a rapid and effective diagnostic tool, given the often quite characteristic presentation of COVID-19 pneumonia [START_REF] Pan | Time course of lung changes at chest CT during recovery from coronavirus disease 2019 (COVID-19)[END_REF][START_REF] Hani | COVID-19 pneumonia: a review of typical CT findings and differential diagnosis[END_REF]. Now that the "first wave" has passed and the pandemic appears to be under control, we propose to review and update the current knowledge on COVID-19 pneumonia imaging.

Role of chest CT in the management of suspected patients

The massive arrival of patients suspected of having COVID-19 in emergency departments has prompted the setting up of "COVID" and "non COVID" pathways, making it necessary to triage patients as early as possible. According to the ESR/ESTI advice paper and recommendations of the French Society of Thoracic Imaging, unenhanced chest CT is currently indicated for patients presenting with dyspnea, polypnea or desaturation in order to refer them to "COVID" or "non COVID" wards, pending RT-PCR results [START_REF] Revel | COVID-19 patients and the radiology department -advice from the European Society of Radiology (ESR) and the European Society of Thoracic Imaging (ESTI)[END_REF]. Chest CT sensitivity for the diagnosis of COVID-19 is greater than 90%, with false-negative findings mostly in patients who are symptomatic for less than 3 days [START_REF] Ai | Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases[END_REF][START_REF] Bernheim | Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection[END_REF]. CT specificity is more variable. Series from China and Italy reported specificity values between 25% and 56% [START_REF] Ai | Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases[END_REF][START_REF] Caruso | Chest CT features of COVID-19 in Rome, Italy[END_REF]. A meta-analysis, including mainly Asian studies, reported pooled sensitivity and specificity of 94% and 37% respectively for the diagnosis of COVID-19 pneumonia [START_REF] Kim | Diagnostic performance of CT and reverse transcriptasepolymerase chain reaction for coronavirus disease 2019: a meta-analysis[END_REF]. Furthermore, this meta-analysis reported a high degree of variability in positive predictive value of chest CT according to prevalence. Depending on whether the prevalence is 1%, 10% or 39%, the positive predictive value would become 1.5%, 14.2% or 48.8%, respectively. Thus, the use of CT as a screening tool in low prevalence areas would lead to a large number of false positives. In addition, it should be noted that inter-reader agreement of chest CT for COVID-19 diagnosis is generally reported to be good or even excellent [START_REF] Yang | Chest CT severity score: an imaging tool for assessing severe COVID-19[END_REF][START_REF] Himoto | Diagnostic performance of chest CT to differentiate COVID-19 pneumonia in non-high-epidemic area in Japan[END_REF].

In practice, chest CT results can lead to three scenarios: (i) when chest CT is very suggestive of COVID-19, the patient will be hospitalized in a COVID-19 isolation ward, and RT-PCR testing will generally confirm the diagnosis; (ii) when chest CT shows an obvious alternate diagnosis (e.g. bacterial lobar pneumonia or left ventricular failure), the patient will be hospitalized in a "non COVID-19" ward; (iii) when chest CT scan is indeterminate, RT-PCR testing along with clinical symptoms will be essential for referral to the most appropriate ward.

Chest CT scans should not be performed for screening purpose in asymptomatic patients.

Neither chest X-ray nor ultrasonography is recommended for the diagnosis of COVID-19, as their performance appears to be significantly inferior to that of CT.

Typical CT presentation

The most typical CT features of COVID-19 pneumonia are bilateral and multifocal groundglass opacities. Lesions classically predominate in the peripheral, posterior and basal part of the lungs (Figure 1) [START_REF] Bernheim | Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection[END_REF]. Other signs have been reported such as the presence of fine reticulations, peribronchovascular thickening, vascular dilatations within pneumonia areas, or architectural distortion [START_REF] Zhao | Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19) pneumonia: a multicenter study[END_REF]. Usually, there are no micronodules, excavations, septal lines, mediastinal lymph node enlargement or pleural effusions. Some infected but asymptomatic patients may have slight ground-glass opacities but these are generally not extensive [START_REF] Inui | Chest CT findings in cases from the cruise ship "Diamond Princess" with coronavirus disease 2019 (COVID-19)[END_REF].

Chest CT appearance of COVID-19 may be quite similar to that of other viral pneumonitis.

However, the peripheral location of the lesions, involvement of the five lobes, the presence of thin reticulations and peribronchovascular thickening would be more frequently found in COVID-19 pneumonitis [START_REF] Bai | Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT[END_REF][START_REF] Li | Comparison of chest CT findings between COVID-19 pneumonia and other types of viral pneumonia: a two-center retrospective study[END_REF]. In influenza pneumonia, nodular or micronodular tree-inbud pattern may be more common, as may pleural effusions [START_REF] Liu | COVID-19 pneumonia: CT findings of 122 patients and differentiation from influenza pneumonia[END_REF].

Atypical CT presentation

In approximately 10% of patients, lung involvement of COVID-19 may present as arciform or pseudonodular consolidation suggesting a pattern of organizing pneumonia [START_REF] Bekci | Reversed halo sign » on 3D CT in COVID-19[END_REF], sometimes with a "reverse halo sign" similar to the one observed in other infectious diseases [START_REF] Martini | Nodular reverse halo sign in active pulmonary tuberculosis: a rare CT feature?[END_REF].

Unilateral presentation is possible in about 20-30% of patients, usually at an early stage before bilateralization of the lesions [START_REF] Ai | Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases[END_REF][START_REF] Shi | Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study[END_REF]. Peribronchovascular or apical predominance is also described (Figure 3) [START_REF] Chung | CT imaging features of 2019 novel coronavirus (2019-nCoV)[END_REF]. When COVID-19 pneumonia occurs in a previously abnormal lung (e.g., with underlying emphysema or fibrosis), CT presentation becomes less specific, making a careful comparison with previous CT examinations, when available, mandatory (Figure 4) [START_REF] Langlet | CT features of pulmonary interstitial emphysema[END_REF].

Evolution of CT findings

Ground-glass opacities tend to progress over time, both in extent and attenuation value, and evolve either towards crazy paving areas (i.e. superimposition of ground-glass and intralobular reticulations), or towards linear and retractile consolidation areas (Figure 2) [START_REF] Bernheim | Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection[END_REF][START_REF] Xiong | Clinical and high-resolution CT features of the COVID-19 infection: comparison of the initial and follow-up changes[END_REF][START_REF] Wang | Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a longitudinal study[END_REF][START_REF] Liang | Evolution of CT findings in patients with mild COVID-19 pneumonia[END_REF]. Lung damage is maximal around day 10 and then generally decreases progressively in size and attenuation value [START_REF] Zhou | Imaging features and evolution on CT in 100 COVID-19 pneumonia patients in Wuhan, China[END_REF]. However, early available data on the late appearance of lung parenchyma are still scarce. While complete resolution seems to be common in patients with mild pneumonia, it seems that many patients, especially those with initial severe disease, still present reticular pattern of fibrotic streaks after more than one month of evolution (Figure 2).

According to a recent study, lung abnormalities could persist beyond one month in 98% of patients [START_REF] Ding | Chest CT findings of COVID-19 pneumonia by duration of symptoms[END_REF]. There is therefore some concern about a significant number of pulmonary fibrotic sequelae, although the proportion is not yet known [START_REF] Zhao | Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19) pneumonia: a multicenter study[END_REF][START_REF] Wang | Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a longitudinal study[END_REF].

Severity signs

The total extent of lung involvement on the first CT examination is correlated with clinical severity [START_REF] Yang | Chest CT severity score: an imaging tool for assessing severe COVID-19[END_REF][START_REF] Xiong | Clinical and high-resolution CT features of the COVID-19 infection: comparison of the initial and follow-up changes[END_REF][START_REF] Li | The clinical and chest CT features associated with severe and critical COVID-19 pneumonia[END_REF]. The French Society of Thoracic Imaging (SIT) recommends grading lung involvement as absent or minimal (<10%), moderate (10-25%), extensive (25-50%), severe (50-75%) or critical (>75%) (Figure 5). The density of pulmonary lesions is also a marker of severity, since lung consolidation areas appear more extensive than ground-glass opacities in critically ill patients [START_REF] Li | The clinical and chest CT features associated with severe and critical COVID-19 pneumonia[END_REF]. Pleural effusion and early architectural distortion with traction bronchiectasis on initial chest CT would also indicate a poor prognosis [START_REF] Zhao | Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19) pneumonia: a multicenter study[END_REF]. A Chinese series suggests that consolidation in upper lobes on initial CT is also associated with poor outcomes [START_REF] Yu | Multicenter cohort study demonstrates more consolidation in upper lungs on initial CT increases the risk of adverse clinical outcome in COVID-19 patients[END_REF].

Complications

Between 15 and 30% of hospitalized patients progress to acute respiratory distress syndrome (ARDS), which is the main cause of mortality in COVID-19. ARDS is characterized in CT by extensive bilateral lung consolidation with a predominance in dependent areas (Figure 5) [START_REF] Huang | Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[END_REF][START_REF] Wang | Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China[END_REF]. In addition, several complications can occur in the clinical course of these patients.

Pulmonary bacterial superinfection will be suspected in case of additional alveolar consolidation areas with pleural effusion and/or enlarged lymph nodes [START_REF] Zhao | Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19) pneumonia: a multicenter study[END_REF]. In a recent study, COVID-19 associated pulmonary aspergillosis was reported in 5 of 19 consecutive patients with ARDS(Figure 6) [START_REF] Koehler | COVID-19 associated pulmonary aspergillosis[END_REF]. However, distinction between COVID-19 and pulmonary aspergillosis lesions with CT remains difficult [START_REF] Rutsaert | COVID-19associated invasive pulmonary aspergillosis[END_REF].

Pulmonary embolism has been reported in COVID-19 patients (Figure 7) [START_REF] Grillet | Acute pulmonary embolism associated with COVID-19 pneumonia detected by pulmonary CT angiography[END_REF][START_REF] Leonard-Lorant | Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels[END_REF][START_REF] Poissy | Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence[END_REF][START_REF] Bompard | Pulmonary embolism in patients with Covid-19 pneumonia[END_REF]. In critically ill patients, there is an exacerbated systemic inflammatory response leading to an hypercoagulability state, reflected by the marked increase of D-dimer serum level in these patients [START_REF] Tang | Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia[END_REF]. The occurrence of pulmonary embolism is mainly reported in intensive care unit patients, based on retrospective studies. The exact prevalence of pulmonary embolism in COVID19 remains unknown, and would require a prospective evaluation, with systematic assessment of clinical symptoms, CT features and D-dimers. Routine CT pulmonary angiography to check for pulmonary embolism is so far not indicated as a first-line diagnostic tool. However, a clinical-radiological discordance (dyspnea and hypoxemia without lung abnormality) or respiratory worsening in a known COVID-19 patient should prompt the use of contrast medium injection. It would be worth assessing the value of routine CT pulmonary angiography in patients with highly elevated D-dimer levels. Finally, radiologists should be aware that pulmonary infarction secondary to pulmonary embolism may be quite similar in appearance to COVID-19 pneumonia (Figure 8).

Specificities in children and pregnant women

In the pediatric population, pulmonary CT involvement is often less extensive than in adults.

There are often no CT abnormalities [START_REF] Song | Clinical features of pediatric patients with coronavirus disease (COVID-19)[END_REF]. In case of lung involvement, ground-glass is the predominant sign [START_REF] Song | Clinical features of pediatric patients with coronavirus disease (COVID-19)[END_REF][START_REF] Zhen-Dong | Clinical and transmission dynamics characteristics of 406 children with coronavirus disease 2019 in China: a review[END_REF]. The "halo sign" is found more frequently than in adults [START_REF] Tang | Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia[END_REF][START_REF] Zhen-Dong | Clinical and transmission dynamics characteristics of 406 children with coronavirus disease 2019 in China: a review[END_REF].

Coinfections, especially viral, are also more frequent [START_REF] Xia | Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults[END_REF].

In pregnant women, there is no evidence of maternal-fetal transmission of SARS-CoV-2 and no specific per or post-partum complications [START_REF] Qiao | What are the risks of COVID-19 infection in pregnant women?[END_REF]. Consolidation might be more common than in the general population [START_REF] Liu | Clinical and CT imaging features of the COVID-19 pneumonia: focus on pregnant women and children[END_REF]. There appears to be no excess mortality related to COVID-19 in pregnant women [START_REF] Schwartz | An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes[END_REF].

Artificial intelligence (AI) in imaging of COVID-19

Machine learning techniques have the potential to dramatically transform medical imaging [START_REF] Waymel | Impact of the rise of artificial intelligence in radiology: what do radiologists think?[END_REF][START_REF] Colevray | Convolutional neural network evaluation of over-scanning in lung computed tomography[END_REF](48). Several deep-learning and radiomics based tools are currently being developed to approach automated diagnosis, quantification of lesion extension and prognostic estimation of COVID19 pneumonia. They show great promise for making positive diagnosis of COVID-19 pneumonia, for automatically quantifying pulmonary lesion extension and for identifying biomarkers that could be of prognostic interest. In a study from the city of Wuhan in China, carried out on a database of 4356 CT scans (30% COVID-19, 40% community pneumonia and 30% non-infectious pneumonia), a deep learning model diagnosed COVID-19 pneumonia with a sensitivity of 90% and a specificity of 96%, allowing reliable differential diagnosis with community acquired pneumonia [START_REF] Li | Artificial intelligence distinguishes COVID-19 from community-acquired pneumonia on chest CT[END_REF]. Huang et al. trained a deep learning algorithm on an annotated database of 842 COVID-19 patients, and tested it on an independent series of 126 patients. The percentages of lung involvement were significantly different for mild, moderate and severe clinical conditions, and automatic quantification also allowed longitudinal follow-up of patients [START_REF] Huang | Serial quantitative chest CT assessment of COVID-19: deep-learning approach[END_REF].

AI certainly has an important role to play in assessing the prognosis of COVID-19 and identifying biomarkers predictive of patient outcomes. For this purpose, several national and international databases are currently being deployed to enable AI models to be trained on massive data.

Conclusion

CT imaging plays a key role in the management of COVID-19 pneumonia, particularly for early evaluation by allowing rapid triage of dyspneic patients, and also in the event of clinical worsening to detect complications, particularly thromboembolic ones. Pulmonary CT extension is correlated with clinical severity and should be assessed in a semi-quantitative manner by the radiologist. In a near future, AI techniques should make it possible to automate the positive diagnosis as well as the quantitative assessment of lesions, and perhaps allow the extraction of biomarkers to predict the outcome of COVID-19 patients.

Legends of figures:

Figure 1 .

 1 Figure 1. 64-year-old man with COVID-19 pneumonia. Unenhanced CT images of the chest

Figure 2 .

 2 Figure 2. 78-year-old woman with COVID-19 pneumonia. (A, B) Initial unenhanced chest CT

Figure 3 .

 3 Figure 3. Unenhanced CT examination in a 26-year-old woman with COVID-19 pneumonia.

Figure 4 .

 4 Figure 4. 75-year-old man with history of chronic bronchiolitis recently diagnosed with

Figure 5 .

 5 Figure 5. Various degrees of lung involvement in COVID-19 pneumonia in four different

Figure 6 .

 6 Figure 6. 59-year-old man with COVID-19 and a 3-fold positive endotracheal swab for

Figure 7 .

 7 Figure 7. 36-year-old woman positive for COVID-19 and pulmonary embolism. CT

Figure 8 .

 8 Figure 8. 74-year-old woman with COVID-19 pneumonia. (A, B) Baseline CT images

Disclosure of interest

The authors declare that they have no competing interest.

Author contributions

All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship.

Informed consent and patient details

The authors declare that this report does not contain any personal information that could lead to the identification of the patients. a quadrangular well-demarcated subpleural consolidation containing central lucencies corresponding to a pulmonary infarction (arrow). (C, D) Follow-up CT images obtained 7 days later show progression of COVID-19 pulmonary lesions with reticulations, fibrotic streaks and architectural distortion (black arrowheads) and persisting thrombus (white arrowhead).


Camille Attané

Catherine Muller
email: catherine.muller@ipbs.fr

Drilling for Oil: Tumor-Surrounding Adipocytes Fueling Cancer

Keywords:

diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Tumor microenvironment: a source of metabolites for cancer cells

Metabolic reprograming is a hallmark of cancer, as defined in 2011 by Hanahan and Weinberg [START_REF] Hanahan | Hallmarks of cancer: the next generation[END_REF], and is a very active research field in the development of new anti-cancer drugs. The metabolic phenotype of cancer cells depends on intrinsic factors such as genetic alterations, specificities of tissue origin and tumor state, but also on extrinsic factors that comprise interactions with the tumor microenvironment (TME) [START_REF] Martinez-Outschoorn | Cancer metabolism: a therapeutic perspective[END_REF]. The metabolic flexibility of cancer cells allows them to use different metabolites to produce energy, maintain their redox status and obtain intermediate metabolites needed for synthesis of biomolecules and cell signaling (for review [START_REF] Martinez-Outschoorn | Cancer metabolism: a therapeutic perspective[END_REF]). The TME is an important source of metabolites that benefit cancer cells, referred to here as metabolic symbiosis (Box 1). These metabolites provided by the TME are used by cancer cells to promote tumor progression [START_REF] Martinez-Outschoorn | Cancer metabolism: a therapeutic perspective[END_REF]. Besides glucose and glutamine, the role of lipids in cancer progression is increasingly highlighted [START_REF] Beloribi-Djefaflia | Lipid metabolic reprogramming in cancer cells[END_REF]. Initially, while most attention was focused on de novo lipogenesis (using glucose and glutamine as substrates), it is now apparent that cancer cells can acquire exogenous free fatty acids (FFA). Recent studies have shown that exogenous FFAs, rather than de novo lipogenesis appear to be the predominant lipid source for cancer cells [START_REF] Balaban | Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer[END_REF][START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF][START_REF] Hosios | Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells[END_REF].

In the TME, the mature adipocytes -the major component of white adipose tissue (WAT)-are a tremendous reservoir of lipids for cancer cells. Distributed throughout the body, WAT is found in close proximity to various invasive solid cancers in humans such as breast, prostate, colon and kidney cancers and melanoma [START_REF] Duong | The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance[END_REF][START_REF] Lengyel | Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors[END_REF][START_REF] Park | Obesity and cancer--mechanisms underlying tumour progression and recurrence[END_REF][START_REF] Clement | Obesity and melanoma: could fat be fueling malignancy?[END_REF]. WAT is specialized in storing and delivering, when needed, energy to demanding tissues (such as liver, muscle or heart). Such functions are ensured by metabolically active cells, the adipocytes. Additionally, WAT is an important endocrine organ that secretes hormones, cytokines, chemokines and growth factors, termed adipokines [START_REF] Fasshauer | Adipokines in health and disease[END_REF]. WAT has recently emerged as a main actor in tumor progression [START_REF] Duong | The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance[END_REF][START_REF] Lengyel | Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors[END_REF][START_REF] Park | Obesity and cancer--mechanisms underlying tumour progression and recurrence[END_REF]. Several soluble factors (such as chemokines or pro-inflammatory cytokines) have been involved in the cross-talk between tumor cells and surrounding WAT, of which some have also been secreted by other components of the TME (such as cancer-associated fibroblasts or tumor-associated macrophages) [START_REF] Quail | Microenvironmental regulation of tumor progression and metastasis[END_REF]. One of the most specific and emerging mechanisms regarding the role of WAT in the TME involves the ability of cancer cells to advantageously exploit the nourishing role of adipocytes. This metabolic symbiosis has now been demonstrated in a wide range of models such as breast, ovarian and prostate cancers and melanoma [START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF][START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF][START_REF] Lazar | Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer[END_REF]. The known association between obesity and cancer mortality clearly reinforces the interest for this research area [START_REF] Renehan | Adiposity and cancer risk: new mechanistic insights from epidemiology[END_REF]. Obesity is characterized by increased adipose depot size, associated to changes at tissue level, including metabolic dysfunctions and is characterized by a sub-inflammatory state [START_REF] Kahn | Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome[END_REF]. Investigations are now beginning to be conducted on whether this state affects metabolic symbiosis.

However, the simple concept of using lipids to provide energy to tumor cells in order to sustain tumor progression is more complex than we initially thought. In this review, we will discuss how tumor cells force adipocytes to deliver lipids and how these lipids promote tumor progression. A particular focus will be on the differences observed in this metabolic symbiosis depending on the cancer type and localization.

Tumor-surrounding adipocytes: a source of lipids for tumor cells

Adipocytes are a major component of the tumor microenvironment

Mature adipocytes are one of the main components of many TMEs. WAT is found in close proximity to invasive cancers such as breast (mammary adipose tissue, MAT), prostate (periprostatic adipose tissue, PPAT), colon (visceral adipose tissue, VAT) or melanoma (subcutaneous adipose tissue, SAT) and cancer cells come into contact with WAT upon crossing the basement membrane. Adipocytes are also present in the TME of hematological malignancies such as acute myeloid leukemia (AML) and multiple myeloma (MM). In fact, the bone marrow (BM) contains bone marrow adipocytes (BM-Ad) that represent around 10% of the total fat mass [START_REF] Cawthorn | Bone Marrow Adipose Tissue Is an Endocrine Organ that Contributes to Increased Circulating Adiponectin during Caloric Restriction[END_REF]. In addition, during the metastatic process, solid tumors might localize to adipocyte-rich microenvironments such as the omentum, a large intra-peritoneal fat pad that extends from the stomach and covers the bowel [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF]. Omental metastases are frequently observed for ovarian, gastric and pancreatic cancers. Furthermore, solid tumors that frequently metastasize to the bones, such as prostate, breast, lung, kidney or melanoma are found in near proximity to BM-Ad. Finally, hematological malignancies also disseminate to VAT, at least in mouse models [START_REF] Ye | Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche[END_REF].

The delipidation of adipocytes is observed at the invasive front of human tumors

Adipocytes neighboring cancer cells display profound phenotypic and functional alterations (Figure 1). Histological images of solid tumors have consistently shown a decrease in both number and size of adipocytes, located at the invasive front compared to adipocytes distant from the tumor (for review [START_REF] Duong | The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance[END_REF][START_REF] Park | Obesity and cancer--mechanisms underlying tumour progression and recurrence[END_REF][START_REF] Nieman | Adipose tissue and adipocytes support tumorigenesis and metastasis[END_REF]). Moreover, at the tumor center, there are elevated fibroblast-like cells suggesting a "dedifferentiation" of adipocytes induced by cancer cells [START_REF] Duong | The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance[END_REF][START_REF] Park | Obesity and cancer--mechanisms underlying tumour progression and recurrence[END_REF][START_REF] Nieman | Adipose tissue and adipocytes support tumorigenesis and metastasis[END_REF]. Using a coculture system, where the two populations are separated by an insert, we found that adipocytes cocultivated with breast tumor cells for 3 to 5 days exhibited a delipidation and decreased expression of adipocyte markers such as Ap2 (FABP4), adiponectin, and resistin [START_REF] Dirat | Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion[END_REF]. Cocultivated adipocytes exhibited an activated phenotype marked by up-regulation of proinflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin (IL)-6, and IL1β [START_REF] Dirat | Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion[END_REF] as well as proteins involved in extra-cellular matrix remodeling like matrix metalloproteinase 11 (MMP11) [START_REF] Dirat | Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion[END_REF][START_REF] Andarawewa | Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front[END_REF]. Such activated phenotypes have been found in vivo at the invasive front of human breast tumors [START_REF] Dirat | Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion[END_REF][START_REF] Andarawewa | Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front[END_REF]. Collectively, these data show that adipocytes are not inert to the surrounding tumor and exhibit specific traits, hence we have named them Cancer-Associated Adipocytes (CAAs). These results initially obtained in breast cancer (BCa), have been confirmed in other models including, prostate [START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF] and ovarian [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF] cancers as well as melanoma [START_REF] Zhang | Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins[END_REF]. In fact, it is now acknowledged that, in all solid tumors, the invasion of proximal adipose tissue by tumor cells leads to profound delipidation of adipocytes, which could ultimately result in the accumulation of fibroblast-like cells, contributing to the so-called desmoplastic reaction-a dense fibrous tissue present around the tumor [START_REF] Duong | The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance[END_REF][START_REF] Park | Obesity and cancer--mechanisms underlying tumour progression and recurrence[END_REF][START_REF] Nieman | Adipose tissue and adipocytes support tumorigenesis and metastasis[END_REF]. Upon exposure to cancer cells in vitro, adipocytes undergo sequential morphological changes: first marked by a decrease in adipocyte size and lipid content as seen above (CAAs) and next by acquiring a fibroblast-like morphology (cells that we named Adipose-Derived Fibroblasts, ADFs) [START_REF] Bochet | Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer[END_REF].

Tumor cells cocultivated with ADFs in two-dimensional or spheroid culture displayed increased invasive capabilities and the presence of ADFs was confirmed in clinical specimens of breast cancer [START_REF] Bochet | Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer[END_REF]. Together, these results underline the extensive phenotypic changes of mature adipocytes that surround cancer cells.

Mechanisms of lipid release from tumor-surrounding adipocytes

The occurrence of CAAs and ADFs is the result of at least two processes, dedifferentiation and induction of lipolysis. In both cases, the characterization of the mechanisms involved is incomplete. In BCa, we have shown a reactivation of the Wnt/catenin pathway in mature adipocytes, in response to tumor-cell-secreted Wnt3a [START_REF] Bochet | Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer[END_REF]. This has also been demonstrated in CAAs in pancreatic cancer [START_REF] Chirumbolo | Can Wnt5a and Wnt non-canonical pathways really mediate adipocyte de-differentiation in a tumour microenvironment?[END_REF]. It is known that this pathway negatively regulates adipose progenitor differentiation along the adipose lineage [START_REF] Bochet | Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer[END_REF]. So, Wnt/catenin pathway activation is used to induce a dedifferentiated state of mature adipocytes that appear to be highly plastic [START_REF] Bochet | Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer[END_REF][START_REF] Chirumbolo | Can Wnt5a and Wnt non-canonical pathways really mediate adipocyte de-differentiation in a tumour microenvironment?[END_REF]. An important mechanism contributing to the delipidation of CAAs is the ability of tumor cells to activate lipolysis in adipocytes [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF][START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF][START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF][START_REF] Sagar | Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue[END_REF][START_REF] Shafat | Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment[END_REF][START_REF] Diedrich | Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1alpha activation[END_REF][START_REF] Wang | Human adipocytes stimulate invasion of breast cancer MCF-7 cells by secreting IGFBP-2[END_REF]. Adipocytes are cells dedicated to storing and releasing lipids, an energy-dependent process known as lipolysis (Box 2). The breakdown of triglycerides (TG) involves the intervention of three consecutive lipases ATGL (Adipose Triglyceride Lipase), HSL (Hormone-sensitive lipase) and MAGL (Monoacylglycerol lipase) ultimately leading to the release of FFA and glycerol. Of note, palmitic, oleic and linoleic acids are the main FFA released through lipolysis [START_REF] Hellmuth | Association between plasma nonesterified fatty acids species and adipose tissue fatty acid composition[END_REF] but the nature of the FFA released could be different depending on the adipose depot (MAT, PPAT, VAT or SAT) or in obese compared to lean subjects [START_REF] Yew Tan | Adipose tissue fatty acid chain length and mono-unsaturation increases with obesity and insulin resistance[END_REF]. Release of these FFA is observed when in vitro differentiated adipocytes or isolated primary adipocytes are incubated with conditioned medium from breast, prostate or ovarian cancer cell lines [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF][START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF][START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. In addition to acute stimulation of lipolysis through phosphorylation and activation of HSL [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF][START_REF] Sagar | Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue[END_REF][START_REF] Shafat | Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment[END_REF], tumor cells can extend lipolysis activation through upregulation of the expression of HSL [START_REF] Lengyel | Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors[END_REF][START_REF] Diedrich | Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1alpha activation[END_REF] and/or ATGL [START_REF] Shafat | Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment[END_REF][START_REF] Diedrich | Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1alpha activation[END_REF][START_REF] Wang | Human adipocytes stimulate invasion of breast cancer MCF-7 cells by secreting IGFBP-2[END_REF]. While it is now admitted that tumor induced lipolysis occurs in adipocytes, the lipolytic factor(s) involved remain(s) to be determined (Figure 1). Catecholamines are major hormones involved in lipolysis induction and have been implicated in the activation of lipolysis by ovarian cancer cell lines [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF] but not in BCa and prostate cancer (PCa) models [START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. Proinflammatory cytokines are also able to cause lipolysis of WAT, a pathway that has been involved in the disappearance of adipose mass during cancer cachexia [START_REF] Das | Adipose triglyceride lipase contributes to cancer-associated cachexia[END_REF]. In mouse models, Ye et al proposed that the lipolysis induced by leukemic stem cells, relocated to VAT, might be due to the secretion of pro-inflammatory cytokines, such as IL-1α, IL-1β, Colony Stimulating Factor 2 (CSF2) and TNFα despite no direct demonstration of this effect having been provided [START_REF] Ye | Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche[END_REF]. Finally, signals emanating from tumor cells could be contained in tumorreleased extracellular vesicles (EV). In pancreatic cancer, EV-contained adrenomedullin lead to phosphorylation and activation of HSL [START_REF] Sagar | Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue[END_REF]. Thus, even if some tumor secreted factors have been proposed to induce lipolysis in adipocytes, these results should be interpreted with caution.

The lipolytic signals could be different depending on the tumor considered and further studies are clearly needed to clarify this issue.

More recently, studies have proposed that lipid transfer from adipocytes to cancer cells could also happen through EV. We have recently demonstrated that mature adipocytes liberate continuously, independently of lipolytic stimuli, EV-containing FFA [START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF] which are taken up by tumor cells (see below). The liberation of EV-containing FFA is amplified byadrenergic stimulation suggesting that this process might also be involved in lipid transfer upon energy deprivation [START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF]. EV are known to transport a large panel of lipid species such as sphingomyelin, cholesterol, lysophosphatidylcholine and eicosanoids [START_REF] Lazar | A new role for extracellular vesicles: how small vesicles can feed tumors' big appetite[END_REF][START_REF] Record | Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies[END_REF] whose implications in adipocytes/cancer crosstalk have never been explored. Finally, Ferrante's team recently showed that adipocytes release EV containing small pieces of lipid droplets (composed of TG and cholesterol ester) that are directly transferred to macrophages in WAT [START_REF] Flaherty | A lipase-independent pathway of lipid release and immune modulation by adipocytes[END_REF]. Again, although this mechanism has not been investigated in cancer, all these innovative studies highlight that the EV "route" should not be neglected in the context of metabolic symbiosis.

Are BM-Ad transformed into CAAs by tumor cells?

As mentioned above, the primary tumor site for hematological malignancies and metastatic site for some cancers is the BM which contains BM-Ad. When considering BM biopsies, the delipidation of BM-Ad at close proximity of cancer cells is not clear. In MM, an increase in the number of preadipocytes as well as increased BM-Ad size have been reported in comparison to control subjects [START_REF] Trotter | Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone[END_REF]. A recent study challenged these results by showing a decrease in adipocyte number with only a slight decrease in BM-Ad area in patients with evolutive disease when compared to controls [START_REF] Liu | Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease[END_REF]. While BM-Ad certainly plays a role in the development of MM, favoring local dissemination and growth [START_REF] Trotter | Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone[END_REF] or the occurrence of osteolytic lesions [START_REF] Liu | Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease[END_REF],

the key features of CAAs are not observed in vivo. In AML, slightly different results have been observed. In a study, comparing control samples to those of patients exhibiting refractory diseases or in remission (70 samples in each group), the patients with active disease were reported to have an increase in the number of small adipocytes yet lacked significant changes in the representation of medium/large BM-Ad [START_REF] Lu | Small bone marrow adipocytes predict poor prognosis in acute myeloid leukemia[END_REF]. By contrast, a dramatic decrease in adipocyte size was observed in VAT colonized by AML cells in vivo [START_REF] Ye | Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche[END_REF] or when AML cells were engrafted in SAT [START_REF] Boyd | Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche[END_REF]. Using human samples and mouse models, Boyd et al reported decreased adipocyte size and frequency in the presence of AML cells in haematopoietically active "red" marrow whilst adipocytes from haematopoietically inactive "yellow" marrow were unaffected [START_REF] Boyd | Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche[END_REF]. The observed changes in BM-Ad favored leukemic cell outgrowth while negatively affecting normal hematopoiesis [START_REF] Boyd | Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche[END_REF]. Absence of decrease in the medium/large adipocytes [START_REF] Lu | Small bone marrow adipocytes predict poor prognosis in acute myeloid leukemia[END_REF] and the elective decrease of BM-Ad in the "red" marrow area [START_REF] Boyd | Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche[END_REF], where there is a constant accumulation of newly formed adipocytes [START_REF] Scheller | Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues[END_REF], suggests that AML cells are more likely to induce a defect of adipogenesis rather than an activation of a lipolytic process in already-formed mature adipocytes. These results are not surprising when the physiology of BM-Ad is considered. Recent reports highlight that BM-Ad are deficient in lipolysis in both mouse [START_REF] Scheller | Bone marrow adipocytes resist lipolysis and remodeling in response to beta-adrenergic stimulation[END_REF] and human [START_REF] Attané | Human bone marrow is comprised of adipocytes with specific lipid metabolism Cell Reports[END_REF] models in accordance with the fact that this fat depot is not sensitive to energy deprivation [START_REF] Devlin | Caloric restriction leads to high marrow adiposity and low bone mass in growing mice[END_REF]. In addition, we demonstrated that the bone marrow mesenchymal stem cells (MSC), differentiated in vitro using classical protocols for in vitro adipogenesis, do not recapitulate the metabolic phenotype of primary human BM-Ad and display effective lipolytic activity [START_REF] Attané | Human bone marrow is comprised of adipocytes with specific lipid metabolism Cell Reports[END_REF]. Therefore, all studies demonstrating a lipid transfer through FFA release between tumor cells (both hematological malignancies and solid tumors) and in vitro differentiated MSC should be interpreted with caution [START_REF] Shafat | Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment[END_REF][START_REF] Diedrich | Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1alpha activation[END_REF][START_REF] Herroon | Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms[END_REF][START_REF] Tabe | Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells[END_REF]. In conclusion, robust results show the occurrence of a lipolytic process with liberation of FFA in various AT at the vicinity of solid tumors, but metabolic symbiosis, if it exists, might be of a different nature in the BM.

Transfer and fate of lipid in tumor cells, a matter of tumor type?

We have seen that tumor-surrounding adipocytes are able to release FFA [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF][START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF][START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF][START_REF] Wen | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer[END_REF] or EVcontaining FFA [START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF]. We will now describe how these lipids are transferred into tumor cells, their metabolic fate inside tumor cells and how they promote tumor progression (Box 3).

Transfer of lipids

Once released by adipocytes, FFA are transferred to cancer cells. This transfer has been demonstrated in several models using isotopically labeled adipocytes [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF] or staining with fluorescent dyes [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF][START_REF] Zhang | Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins[END_REF][START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF][START_REF] Wen | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer[END_REF][START_REF] Gazi | Direct evidence of lipid translocation between adipocytes and prostate cancer cells with imaging FTIR microspectroscopy[END_REF][START_REF] Kwan | Subcutaneous adipocytes promote melanoma cell growth by activating the Akt signaling pathway: role of palmitic acid[END_REF][START_REF] Tan | Adipocytes fuel gastric cancer omental metastasis via PITPNC1mediated fatty acid metabolic reprogramming[END_REF]. Down-regulation of ATGL or HSL expression in adipocytes inhibit the accumulation of lipids in cocultivated BCa cells as compared to control adipocytes [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF]. This decrease in lipid transfer is associated to a decreased effect of adipocytes on BCa cell proliferation and migration, thereby demonstrating that adipocytes alter cancer cell behavior through FFA release [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF]. Identifying the membrane transporters involved in FFA uptake is another approach to demonstrate their direct implication in tumor progression. Several fatty acid transporters have been involved in FFA transfer into cancer cells suggesting cancer type differences. CD36 (FAT, Fatty acid translocase), has been proposed as a prognostic marker in various cancers, mostly of epithelial origin (breast, prostate, ovary and colon) as well as in hepatic carcinoma and gliomas [START_REF] Hale | Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression[END_REF][START_REF] Nath | Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers[END_REF][START_REF] Pascual | Targeting metastasis-initiating cells through the fatty acid receptor CD36[END_REF][START_REF] Watt | Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer[END_REF]. Ovarian cancer cells co-cultured with primary human omental adipocytes express high levels of CD36 and down-regulation of CD36 expression or function prevented the deleterious effect of adipocytes on tumor progression [START_REF] Ladanyi | Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis[END_REF]. Similar effects are observed in PCa when CD36 is inhibited [START_REF] Watt | Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer[END_REF]. The role of long-chain fatty acid transport protein (FATP), in particular FATP1, has been shown to transfer FFA from adipocytes to melanoma cells. Pharmacological inhibition of FATPs with the small molecule Lipofermata abrogates this transfer and reduces melanoma growth and invasion [START_REF] Zhang | Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins[END_REF]. Oncomine analysis shows that high FATP1 expression is correlated with decreased survival in melanoma [START_REF] Zhang | Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins[END_REF] while it is not the case for PCa [START_REF] Watt | Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer[END_REF]. Finally, fatty acid binding proteins (FABPs), small proteins that bind FFA and facilitate their intracellular transport, have also been involved in lipid transfer from adipocytes to ovarian cancer cells. Nieman and collaborators were the first to show that FABP4 is overexpressed in ovarian cancer cells cocultivated with adipocytes and its inhibition reduced both lipid accumulation in cancer cells and adipocyte-mediated invasion in vitro or metastasis in vivo [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF]. Other FABPs are likely to facilitate the uptake of exogenous FFA into cancer cells, in particular FABP5 and FABP7 as they influence lipid uptake in BCa cell lines [START_REF] Bensaad | Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation[END_REF][START_REF] Guaita-Esteruelas | The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5[END_REF]. The FFA contained in EV are also taken up by tumor cells [START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF]. We can therefore conclude that several transmembrane and intracellular transporters are involved in lipid transfer. Once clinically validated, targeting FFA uptake may be an effective strategy for treating invasive solid tumors that evolved in an adipocyte-rich microenvironment.

Fatty acid storage and mobilization

Once taken up, FFAs can act directly as substrates for a range of metabolic pathways including mitochondrial oxidation (as discussed below) or converted into neutral lipids (mainly TG) and stored in small lipid droplets (LD) as observed in breast [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF], prostate [START_REF] Balaban | Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer[END_REF][START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF][START_REF] Watt | Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer[END_REF] and ovarian [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF] cancers and melanoma [START_REF] Lazar | Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer[END_REF][START_REF] Zhang | Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins[END_REF][START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF] to avoid cytotoxicity induced by FFA [START_REF] Petan | Lipid Droplets in Cancer: Guardians of Fat in a Stressful World[END_REF]. The ability of tumor cells to progressively liberate FFA, locally or at distance, is key to the support of tumor progression. Recent evidence showed that cancer cells possess lipolytic activity (Box 3).

Expression of ATGL is upregulated in BCa cells cocultivated with adipocytes in vitro and in cancer cells that are in close contact to adipocytes at the invasive front of human BCa in vivo [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. Decreasing ATGL expression in cocultivated BCa cells impaired lipolysis and reduced the pro-invasive effect of adipocytes [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. A higher ATGL expression was also observed in pancreatic tumors from obese patients (with increased visceral adiposity) and exhibiting higher tumor-surrounding desmoplasia [START_REF] Grace | Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma[END_REF]. It has to be noted that, independently of coculture of adipocytes, the role of ATGL in tumor progression is largely debated with elevated expression in some tumor types whereas down-regulation has been reported in others (for review [START_REF] Vegliante | Hints on ATGL implications in cancer: beyond bioenergetic clues[END_REF]).

Very few data are available on the function of HSL in the context of adipocyte/cancer cell crosstalk, with the exception of its upregulation in BCa cells when cocultivated with adipocytes in vitro [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. Compelling arguments demonstrate that MAGL, the enzyme involved in the last step of lipolysis, is overexpressed in aggressive cancers including melanoma, ovarian, prostate and breast cancer [START_REF] Nomura | Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer[END_REF][START_REF] Nomura | Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis[END_REF]. These initial studies by Nomura et al have clearly highlighted that FFA, taken up or newly synthesized in cancer cells, are immediately converted into neutral lipid stores and that their intracellular utilization is dependent on their release [START_REF] Nomura | Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer[END_REF][START_REF] Nomura | Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis[END_REF]. The importance of MAGL in cancer progression has been confirmed by other studies [START_REF] Hu | Monoacylglycerol lipase promotes metastases in nasopharyngeal carcinoma[END_REF][START_REF] Zhang | Monoacylglycerol Lipase: A Novel Potential Therapeutic Target and Prognostic Indicator for Hepatocellular Carcinoma[END_REF]. The regulation of MAGL function and expression in cancer cells cocultivated with adipocytes has only been studied once and showed a slight upregulation of its expression in cocultivated cells [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. Beside classic lipolysis, lipophagy defined by the lysosomal degradation of TG carried out by lysosomal acid lipase, is an alternate mechanism allowing TG hydrolysis which was initially demonstrated in hepatocytes [START_REF] Singh | Autophagy regulates lipid metabolism[END_REF]. Some preliminary studies suggest that lipophagy might be used by cancer cells [START_REF] Maan | Lipid metabolism and lipophagy in cancer[END_REF]. In colon cancer, mobilization of intracellular lipid stores in cells cocultivated with adipocytes result from such a process [START_REF] Wen | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer[END_REF]. We recently demonstrated that adipocyte EV-derived FFA taken up and stored in LD by melanoma cells are released by lipophagy and not by lipolysis [START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF]. In conclusion, LD act as switches that coordinate lipid storage and liberation in order to support cancer progression. The mechanisms involved are under characterization and are accompanied by new and exciting potential therapeutic targets [START_REF] Attane | Metabolic remodeling induced by adipocytes: a new Achilles' heel in invasive breast cancer?[END_REF].

Fatty acid oxidation: coupled or non-coupled to ATP production?

Adipocyte-released FFA taken up by cancer cells or released from TG stores can be transferred to mitochondria to be oxidized, a metabolic pathway called fatty acid oxidation (FAO) (Box 3).

The last decade of studies has underpinned the role of this metabolic pathway in cancer [START_REF] Carracedo | Cancer metabolism: fatty acid oxidation in the limelight[END_REF].

Coculture with adipocytes lead to increased FAO in an array of cancers including melanoma [START_REF] Zhang | Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins[END_REF], ovarian [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF], prostate [START_REF] Balaban | Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer[END_REF][START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF], breast [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF], colon [START_REF] Wen | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer[END_REF] and gastric [START_REF] Tan | Adipocytes fuel gastric cancer omental metastasis via PITPNC1mediated fatty acid metabolic reprogramming[END_REF] cancers. The entry of FFA into mitochondria is dependent on carnitine palmitoyltransferase 1 (CPT1). The expression of the CPT1a isoform is increased by adipocytes in breast [START_REF] Balaban | Adipocyte lipolysis links obesity to breast cancer growth: adipocytederived fatty acids drive breast cancer cell proliferation and migration[END_REF][START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF] and ovarian [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF] cancers. Moreover, increased mitochondria biogenesis is observed in BCa cells cocultivated with adipocytes [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. All these mechanisms are likely to contribute to increased FAO. Treating BCa cells with a pharmacological inhibitor of CPT1a, etomoxir (ETO), in addition to downregulating its expression, inhibits the invasive capacities of the cancer cells in vitro as well as their metastatic capacities in vivo [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. Pharmacological inhibition of CPT1 also restores the sensitivity of colon cancer to antiangiogenic therapies [START_REF] Iwamoto | Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance[END_REF]. In fact, treatment-induced hypoxia increases the expression of lipid transporters and FAO-related genes that rescues cell death only in tumors adjacent to adipose depots [START_REF] Iwamoto | Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance[END_REF]. These results directly demonstrate the link between the FAO activity and effects of adipocytes. By contrast, while coculture increases FAO in PCa cells, only a slight decrease of invasiveness of cocultivated tumor cells was observed in ETOtreated cells [START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF]. These results demonstrated that transferred FFA are not only used for FAO but promote invasive capacities by different mechanisms (see below). Regarding EV, exposure of melanoma cells to adipocyte-secreted EV (Ad-EV) was found to induce lipid accumulation and stimulates FAO and mitochondrial biogenesis [START_REF] Lazar | Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer[END_REF][START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF]. Ad-EV contains FFA as well as proteins involved in FAO [e.g., HADHA (trifunctional enzyme subunit alpha) and HCDH (Hydroxyacyl-coenzyme A dehydrogenase)], thus providing both the enzyme and substrate to tumor cells, in order to increase their migratory and invasive capacities [START_REF] Lazar | Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer[END_REF][START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF]. In obesity, the heightened effect of Ad-EV on melanoma aggressiveness does not depend on increased expression of FAO-related enzymes but is due to an increased content and transport of FFA [START_REF] Lazar | Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer[END_REF][START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF]. As EV diffuse through tissues and circulate throughout the organism, they may influence tumors not only at proximity to AT, but also at distance to help establish metastatic niches. Further experiments are needed to explore this promising hypothesis.

Convincing results have now been obtained in a wide range of models that link coculture with adipocytes or exposure to Ad-EV to increased FAO, a metabolic remodeling that promotes cancer progression in vitro and in vivo. A question remains: how does increased FAO promote cancer progression? FAO generates coenzymes used by the electron transport chain to produce ATP (Box 3). FAO produces twice as much ATP per mole as oxidation of glucose [START_REF] Carracedo | Cancer metabolism: fatty acid oxidation in the limelight[END_REF]. In the first article reporting a lipid transfer between tumor-surrounding adipocytes and cancer cells, Nieman's team proposed that the increased FAO is used for energy production in order to promote tumor growth, despite ATP production not being measured [START_REF] Nieman | Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[END_REF]. This concept, validated in wider studies, directly demonstrates enhanced ATP production in melanoma [START_REF] Zhang | Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins[END_REF][START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF], omental metastasis of gastric cancer [START_REF] Tan | Adipocytes fuel gastric cancer omental metastasis via PITPNC1mediated fatty acid metabolic reprogramming[END_REF], and in colorectal cancer growing in an adipose environment [START_REF] Iwamoto | Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance[END_REF]. Increased ATP production stimulates tumor growth and invasion [START_REF] Zhang | Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins[END_REF][START_REF] Clement | Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells[END_REF], promotes resistance to cell-death induced anoikis [START_REF] Tan | Adipocytes fuel gastric cancer omental metastasis via PITPNC1mediated fatty acid metabolic reprogramming[END_REF] and confers resistance to antiangiogenic drugs [START_REF] Iwamoto | Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance[END_REF] (Figure 2A). However, in other models, FAO could be uncoupled with ATP production, despite the fact that inhibiting FAO by ETO inhibits invasion [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. In BCa cells cocultivated with adipocytes, a decrease in mitochondrial respiration associated to decreased ATP content was observed [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. This uncoupling was due to enhanced expression of the uncoupling protein 2 as well as the ATPase inhibitory factor 1 [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF]. Adipocytes also induced FAO without increasing respiration or ATP production in CD36+ leukemic cells that colonized VAT [START_REF] Ye | Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche[END_REF] or in cocultivated colon cells [START_REF] Wen | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer[END_REF]. Thus, in these models, increased FAO by adipocytes was not used for ATP production to promote invasive capacities [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF], growth [START_REF] Wen | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer[END_REF] or to confer drug resistance [START_REF] Ye | Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche[END_REF].

Increased FAO associated to decreased mitochondrial respiration could therefore contribute to accumulation of acetyl-CoA. Increasing evidence demonstrates the links between acetyl-CoA, histone acetylation and control of gene expression [START_REF] Mcdonnell | Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation[END_REF][START_REF] Sivanand | Spatiotemporal Control of Acetyl-CoA Metabolism in Chromatin Regulation[END_REF]. Thus, this FAO-derived product could contribute to epigenetic changes favoring the pro-invasive effect of adipocytes [START_REF] Wang | Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells[END_REF][START_REF] Ye | Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche[END_REF][START_REF] Wen | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer[END_REF]. Moreover, acetyl-CoA is also involved in the synthesis of ketone bodies, FFA and cholesterol [START_REF] Pietrocola | Acetyl coenzyme A: a central metabolite and second messenger[END_REF] which could also influence tumor behavior. FAO also contributes to the NADPH pool, critical for regeneration of the GSH antioxidant system to maintain redox balance and survival [START_REF] Carracedo | Cancer metabolism: fatty acid oxidation in the limelight[END_REF][START_REF] Pike | Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells[END_REF] (Figure 2B).

Other effects of FFA taken up by tumor cells

As mentioned above, we showed that FAO induced by coculture with adipocytes is not always the key event responsible for the increased aggressiveness of cancer cells. This is particularly the case in PCa where FFA taken up by tumor cells increase the expression of the pro-oxidant enzyme NADPH oxidase 5 (NOX5) leading to elevated reactive oxygen species (ROS) [START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF].

ROS subsequently activate the HIF1/MMP14 (Hypoxia Inducible Factor 1/Matrix Metalloproteinase 14) signaling pathway, which is responsible for the increased tumor cell invasion induced by adipocytes (Figure 2C). Interestingly, this study is one of the first to show that the metabolic symbiosis might be magnified by obesity [START_REF] Laurent | Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress[END_REF]. In obesity, tumor-surrounding adipocytes, isolated from PPAT of lean and obese patients, are more prone to deliver lipids to tumor cells and to activate the NOX5/HIF1/MMP14 signaling pathway. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results. Lastly, FFA can also bind to transcriptional factors, regulating their function and leading to a transcriptional regulation of cancer cells towards acquisition of more aggressive traits (for review [START_REF] Comba | Basic aspects of tumor cell fatty acid-regulated signaling and transcription factors[END_REF]). These numerous studies emphasize that, despite increased FAO seeming like the most evident pathway explaining the link between lipid transfer and tumor progression, other mechanisms might exist. The different mechanisms coupling FFA transfer to tumor progression are summarized in Figure 2.

Concluding Remarks

Adipocytes are major components of the TME in a large number of cancers and their role in tumor progression is increasingly recognized. Although growing evidence shows that cancer cells are likely using this lipid reservoir in order to promote tumor progression, several questions remain unanswered (see Outstanding Questions). Most studies reported in this review use adipocytes obtained from pre-adipocyte cell lines or isolated adipose progenitors differentiated in vitro, very useful as "first step" models to decipher adipocyte-cancer cell crosstalk. However, these models do not completely reflect the physiology of mature adipocytes within the organism. Additionally, accumulating work pinpoints the existence of adipose depots specificity in terms of secretion patterns and metabolic behavior, as exemplified here in BM-Ad. Further experiments are clearly needed using primary adipocytes isolated from specific adipose depots surrounding each tumor type. Current studies also suggest that cancer type matters for the transfer and fate of FFA delivered by adipocytes, an issue that needs to be addressed more systematically. Finally, it is important to consider that evidence of this metabolic symbiosis existing in animal and human tumors in vivo, or amplified in an obese state is still sparse. Once well established, the metabolic symbiosis between cancer cells and adipocytes will undoubtedly offer new therapeutic avenues in the treatment of cancer in obese and non-obese patients. Box 1: Metabolic symbiosis in the TME Sonveaux and colleagues were the first to demonstrate metabolic cooperation within the TME. Indeed, they showed that, in hypoxic regions, cancer cells use glucose to produce lactate which is then transferred and used in cancer cells present in well-oxygenated regions [START_REF] Sonveaux | Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice[END_REF]. Then, Lisanti's group proposed that cancer-associated-fibroblasts (CAFs) displayed increased anaerobic glycolysis in response to tumor cell signaling leading to lactate release which is in turn used in tumor cells, a process known as the "Reverse Warburg effect" [START_REF] Martinez-Outschoorn | Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth[END_REF]. Lactate taken up by oxidative cancer cells is converted into pyruvate to fuel tricarboxylic acid (TCA) cycle and this effect is associated with increased tumor growth [START_REF] Sonveaux | Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice[END_REF][START_REF] Martinez-Outschoorn | Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth[END_REF]. More recently, beta hydroxybutyrate, a ketone body produced from acetyl CoA, was also shown to be involved in the metabolic crosstalk between BCa cells and adipocytes. Indeed, mammary adipocytes release beta hydroxybutyrate which is taken up by cancer cells and promotes tumorigenesis through regulation of histone acetylation and gene expression [START_REF] Huang | Adipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via beta-hydroxybutyrate[END_REF]. In addition to lactate and beta hydroxybutyrate, cells present in the TME can release amino acids. Ovarian cancer cells induce glutamine release by CAFs which is transferred in cancer cells to promote tumor growth [START_REF] Yang | Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth[END_REF].

Adipocytes can also release glutamine which is taken up by cancer cells to support proliferation in pancreatic cancer [START_REF] Meyer | Adipocytes promote pancreatic cancer cell proliferation via glutamine transfer[END_REF] or to induce resistance to chemotherapy in leukemia cells [START_REF] Ehsanipour | Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine[END_REF]. Other amino acids such as alanine, arginine and cysteine are involved in the metabolic symbiosis in the TME (for review [START_REF] Lyssiotis | Metabolic Interactions in the Tumor Microenvironment[END_REF]). Importantly, EVs released by cells of the TME can also carry metabolites including amino acids, lipids and TCA cycle intermediates that are utilized by cancer cells to promote tumor growth [START_REF] Zhao | Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism[END_REF].

Box 2: Regulation of lipolysis

Lipolysis corresponds to the hydrolysis of TG in three sequential steps producing glycerol and three molecules of FFA. The first step consists of the hydrolysis of TG to DG and FFA carried out by ATGL (Adipose Triglyceride Lipase), then HSL (Hormone-sensitive lipase) converts DG into MG and FFA and lastly MG are hydrolyzed into glycerol and FFA by MAGL (Monoacylglycerol lipase) [START_REF] Lafontan | Lipolysis and lipid mobilization in human adipose tissue[END_REF].

Lipolysis is activated in the fasted state by catecholamines (adrenaline and noradrenaline). The latter activates beta-adrenergic receptors which promote adenylyl cyclase activation and the production of cyclic adenosine monophosphate (cAMP) followed by protein kinase A (PKA) activation. Natriuretic peptides (atrial natriuretic peptide and brain natriuretic peptide) are also important lipolysis activators. They bind and activate type A natriuretic peptide receptors which possess guanylyl cyclase activity and produce cyclic guanosine monophosphate which activates protein kinase G (PKG). PKA and PKG phosphorylate HSL inducing its translocation to the lipid droplet and perilipin 1 (PLIN1) leading to modification of LD surface that facilitates the action of lipases. In the basal state, PLIN1 sequesters comparative gene identification-58 (CGI-58), an ATGL co-activator. After PLIN1 phosphorylation, CGI-58 is released and interacts with ATGL to allow full activation of the lipase. ATGL is also regulated independently of PKA or PKG through G0/G1 switch gene 2 (G0S2) which acts as a competitive inhibitor in the binding of CGI-58. PKA activation also mediates HSL phosphorylation that favors its association with lipid droplets and its activity. Beside catecholamines and natriuretic peptides, other signals are known to activate lipolysis such as growth hormone and proinflammatory cytokines.

Box 3: Transfer and fate of lipids in tumor cells

Several trans-membrane transporters or proteins involved in FFA intra-cellular trafficking have been involved in the transfer of lipids into tumor cells. Once taken up, FFA can be stored as neutral lipids in lipid droplets. Tumor cells possess the ability to liberate FFA overtime to support tumor progression. This mainly involves the lipolytic pathway, although some recent studies also report the implication of lipophagy.

Fatty acyl CoA present in the cytoplasm can be transported into the mitochondria through CPT1 and CPT2 to be oxidized and to produce energy. Acyl-CoA are oxidized by a series of cycles.

Each cycle consists of four reactions cleaving two carbons from the acyl-CoA to release acetyl-CoA, FADH2 and NADH (Figure I). Acetyl-CoA enters the TCA cycle, which comprises a series of chemical reactions producing redox coenzymes FADH2 and NADH through the oxidation of acetyl-CoA. These coenzymes and those produced by each FAO cycle are then used in the electron transport chain (ETC, aka oxidative phosphorylation) to produce adenosine triphosphate (ATP). The ETC is composed of four large complexes labeled I to IV that couple transferred electrons with the transfer of protons across a membrane. This creates an electrochemical proton gradient that drives the synthesis of ATP by ATP synthase (aka complex V). Mitochondrial oxidative phosphorylation is incompletely coupled with ATP production when the proton gradient is dissipated by the mitochondrial inner membrane proton channels, uncoupling protein (UCP). This results in a proton leak across the inner mitochondrial membrane and return to the mitochondrial matrix independently of ATP synthase and thereby without ATP production.

Importantly, mitochondria are a main source of cellular reactive oxygen species (ROS) and mitochondrial uncoupling was proposed as a protective mechanism against mitochondrial oxidative damage by reducing the production of ROS (for review [START_REF] Cadenas | Mitochondrial uncoupling, ROS generation and cardioprotection[END_REF]).

Figure I. Transfer and fate of lipids in tumor cells.

FFA can be taken up by several membrane transporters and stored as TG or directly transferred in the mitochondria to be oxidized. Tumor cells can also release FFA overtime through TG store mobilization through lipolysis or lipophagy. Once inside mitochondria, FFA are oxidized to produce redox coenzymes and acetyl-CoA which enter the TCA cycle. Redox coenzymes are finally used in the ETC for ATP production.

Figure 1 .

 1 Figure 1. Tumor progression promoted by tumor cell lipid uptake released by adipocytes at the invasive front. Tumor cells release lipolytic signals (e.g., catecholamines, proinflammatory cytokines, adrenomedullin, or other unknown signals) to transform adipocytes into CAAs that exhibit dedifferentiation, delipidation, and an activated phenotype. Delipidation is mainly due to the ability of cancer cells to activate lipolysis in adipocytes. In turn, adipocytes liberate FFA (and potentially other lipids), but also EV-containing FFA. Such lipids are internalized by tumor cells and trigger lipid metabolic reprogramming to promote tumor progression.

Figure 2 .Fatty

 2 Figure 2. Involvement of FAO and beyond in tumor progression: current mechanisms. Depending on the type of cancer, FFAs transferred to tumor cells promote tumor progression through different mechanisms. (A) In melanoma, ovarian, metastatic or gastric cancer models, the increased FAO induced by coculture has been described to be coupled to ATP production, resulting in metabolic remodeling and leading to enhanced tumor progression. (B) In BCa, AML, and colon cancer, FAO could be uncoupled to ATP production despite the fact that

Acknowledgement:

The authors thank Charlotte Somes for English editing of the manuscript. Studies performed in our laboratory are supported by the "Fondation de France, the « Fondation ARC (Association pour la recherche sur le cancer) », the « Fondation Toulouse Cancer Santé », « Ligue Contre le Cancer » and the « Société Française de Dermatologie ».