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Microenvironment, Cancer and Adipocytes

Catherine Muller

Group Leader

Cancer is a tissue-based disease in which malignant cells interact 
dynamically with normal cell types. Adipose tissue is found at proximity of numerous invasive cancers and obesity is a cause of increased cancer mortality. The goal of our group is to characterize the role of tumor-surrounding adipocytes in cancer progression and the molecular mechanisms involved in lean and obese conditions.

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Growing evidence indicates that obesity is associated with increased cancer risk and negatively impacts cancer recurrence and survival. Adipose tissue (AT) is frequently found at close proximity to invasive tumours including breast and prostate cancer as well as melanoma. Aside from their energy-storing function, adipocytes, the main cellular component of adipose tissue (AT), are also active endocrine cells that secrete a large variety of molecules (called adipokines), which include growth factors, chemokines and pro-inflammatory molecules. In obesity, the normal balance of these secretions is disrupted. Adipocytes are therefore excellent candidates to influence tumor behavior in a paracrine manner and could prove to be critical for tumor survival, growth, metastasis and response to therapy. Therefore, the main goal of our team is to investigate the role of adipocytes in cancer progression and to characterize the molecular mechanisms involved.

First, we demonstrated that mature adipocytes promote the initial homing of prostate tumor cells to surrounding AT through the secretion of the chemokine MCP-3/CCL7, a process that is highly regulated by obesity (Nature Communications 2016). Once tumor cells invade AT, they dramatically impact tumor-surrounding adipocytes, which then exhibit a modified phenotype and specific biological features, a process that is observed for all tumor types. We therefore named these adipocytes "Cancer-Associated Adipocytes" (CAA), a term that is now widely used by the scientific community (more than 200 citations for our 2011 Cancer Research paper). CAAs modify cancer cell characteristics/phenotype leading to more aggressive behavior. Their effect is mediated through secretion of proteases and pro-inflammatory cytokines, and by modulating cancer cell metabolism through transfer of free fatty acids released by CAAs upon exposure to tumor secretions (Cancer Research 2011, 2013; JCI Insight, 2017). In addition to soluble factors, tumor-surrounding adipocytes also use exosomes (small vesicles that can contain microRNAs, lipids and proteins), which are shuttled to cancer cells to promote cancer aggressiveness (Cancer Research, 2016). Finally, we recently demonstrated that CAAs favor breast cancer resistance to conventional chemotherapy, a process that could also contribute to the poor prognosis of obese patients. 

Taken together, these results underline the innovative concept that adipocytes contribute to a highly complex vicious cycle orchestrated by cancer cells to promote tumor progression and resistance to treatment, this deleterious crosstalk being amplified in obesity. Characterizing this crosstalk in depth in order to develop new therapeutic strategies is the current main goal of our team. 

 

Main publications

  • Wang YY et al. (2017). Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2: e87489
  • Lazar I et al. (2016) Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and cancer. Cancer Res 76:4051-7
  • Laurent V et al. (2016) Periprostatic adipose tissue acts as a driving force for the progression of prostate cancer in obesity. Nature Commun 7:10230
  • Bochet L et al. (2013) Adipocyte-Derived Fibroblasts promote tumor progression and contribute to desmoplastic reaction in breast cancer. Cancer Res 73:5657-68
  • Dirat B et al. (2011) Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 71:2455-2465

 

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Section of invasive breast tumor (mauve) coming into contact of mature adipocytes (white discs). The adipocytes at close proximity of cancer cells exhibit a decrease in size and lipid content (arrows).

 

Lazar I, Clement E, Dauvillier S, Milhas D, Ducoux-Petit M, Le Gonidec S, Moro C, Soldan V, Dalle S, Balor S, Golzio M, Burlet-Schiltz O, Valet P, Muller C, Nieto L* (2016) Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and cancer. Cancer Res 76:4051-7 National Press Release CNRS (in french), Highlighted in Nature Reviews Endocrinology

 

Laurent V, Guérard A, Mazerolles C, Le Gonidec S, Toulet A, Nieto L, Zaidi F, Majed B, Garandeau D, Socrier Y, Golzio M, Cadoudal T, Chaoui K, Dray C, Montsarrat B, Sciltz O, Wang YY, Couderc C, Valet P, Malavaud B, Muller C* (2016) Periprostatic adipose tissue acts as a driving force for the local invasion of prostate cancer in obesity: role of the CCR3/CCL7 axis. Nat Commun 7:10230 National Press Release CNRS, Highlighted in Nature Reviews Cancer and Nature Reviews Urology

 

Laurent V, Nieto L, Valet P, Muller C* (2014) Adipose tissue and cancer: a high risk tandem. Med Sci (Paris) 4:398-404 (in French, invited review)

 

Steunou A L, Ducoux-Petit M, Lazar I, Monsarrat B, Erard M, Muller C, Clottes E, Burlet-Schiltz O, andNieto L* (2013) Identification of the hypoxia-inducible factor 2alpha nuclear interactome in melanoma cells reveals master proteins involved in melanoma development. Mol Cell Proteomics 12:736-748

 

Fallone F, Britton S, Nieto L, Salles B, and Muller C* (2013) ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression. Oncogene 32:4387-4396

 

Bochet L, Lehuede CDauvillier S, Wang YY, Dirat B, Laurent V, Dray C, Guiet R, Maridonneau-Parini I, Le Gonidec S, Couderc B, Escourrou G, Valet P, Muller C* (2013) Adipocyte-Derived Fibroblasts promote tumor progression and contribute to desmoplastic reaction in breast cancer. Cancer Res 73:5657-68 (Press release INSERM/CNRS)

 

Valet P and Muller C* (2013) Adipose Tissue and Cancer :a risked relationship. Correspondances En Métabolismes, Hormones, Diabètes Et Nutrition 17:258-262 (in French, invited review)

 

Muller C* (2013) Tumour-surrounding adipocytes are active players in breast cancer progression. Ann Endocrinol (Paris) 74:108-10 (invited review)

 

Muller C*Nieto L, Valet P (2013) Unraveling the local influence of tumor-surrounding adipose tissue on tumor progression: cellular and molecular actors involved. In “Adipose Tissue and Cancer” (Editor M. Kolonin, Springer edition), p 121-46. (invited contribution)

 

Wang YY., Lehuédé C., Laurent V., Dauvillier S., Dirat B., Bochet L., Escourrou G., Valet P., Muller C* (2012) Adipose tissue and epithelial cancer cells: a dangerous dynamic duo in breast cancer. Cancer Lett 324:142-51 (invited review)

 

Bochet L, Meulle A, Imbert S, B. Salles, P. Valet, Muller C* (2011) Cancer-associated adipocytes promote breast tumor radioresistance. Biochem Biophys Res Commun 411:102-6

 

Masson O, Prébois C., Derocq D., Meulle A., Dray C., Daviaud D., Quilliot D., Valet P., Muller C., Liaudet-Coopman E* (2011) Cathepsin-D, a Key Protease in Breast Cancer, Is Up-Regulated in Obese Mouse and Human Adipose Tissue, and Controls Adipogenesis. PLoS ONE 6(2):e16452

 

Dirat B., Bochet L., Dabek M., Daviaud D., Dauvillier S., Majed B., Wang YY, Meulle A., Salles B., Le Gonidec S., Garrido I., Escourrou G., Valet P., Muller C* (2011) Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 71: 2455-2465 (National Press release INSERM/CNRS, Top 1 % Web of science)

 

Members of the “Microenvironment Cancer et Adipocytes” are in bold * Corresponding author

 

Collaborations

Research Labs 

  • Pr Philippe VALET and Dr Anne BOULOUMIE, Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U858, TOULOUSE, FRANCE 
  • Dr Charles DUMONTET, Centre de Recherche en Cancérologie de Lyon - INSERM U 1052 , LYON, FRANCE 
  • Dr Lionel LARUE, Institut Curie, PARIS, FRANCE 

 

Translational Programs

In prostate cancer, a strong collaboration has been established with the Urology Department (Pr Bernard MALAVAUD and Dr Mathieu ROUMIGUIÉ) as well as the Radiology department (Dr Daniel PORTALES).

 

In breast cancer, a collaboration has been established with Dr Inger THUNE’s team.

In prostate cancer, a collaboration has been established with the Orthopedic surgery Department in order to study bone metastasis (Pr Jean-Michel LAFOSSE and Dr Nicolas REINA)

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