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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

  • Lehuédé C et al. (2019) Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP). Breast Cancer Res. 21:7.
  • 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.
  • 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).

 

Scientists

Catherine Muller

Professor University of Toulouse

Laurence Nieto

Professor in Molecular Biology - University of Toulouse

Frederique Fallone

Associate Professor in Toxicology - University of Toulouse

Delphine Milhas

Associate Professor in Molecular Biology - University of Toulouse

Research Assistants

Stéphanie Dauvillier

University Engineer

Olivia Melyon

CNRS Fixed-term contract Engineer

Mohammed Moutahir

CNRS Technician

Clinicians

Charlotte Vaysse

Associate Professor in Oncology Surgery - IUCT/University of Toulouse

Post-doctoral fellows

Camille Attané

Fondation de France Fellow

David Esteve

Fellow of the Fondation pour la Recherche Médicale

PhD students

Emily Clement

Fondation ARC Fellow

Mathieu Roumiguie

Assistant in Urology - University of Toulouse

Selected publications


This is short list of our main recent contributions to microenvironment, cancer and adipocytes research. Other papers and reviews are available through Pubmed.

 

Our latest reviews

  • Lazar I*, Clement E* et al. 2018. A new role for extracellular vesicles: how small vesicles can feed tumors' big appetite. Journal of Lipid Research. (Upon invitation) 
  • Fallone F et al. 2018. Breast cancer, obesity and adipose tissue: a high-risk combination. Med Sci (Paris). (in French, invited review) 
  • Attané C et al. 2018. Metabolic remodeling induced by adipocytes: a new Achilles' heel in invasive breast cancer? Curr Med Chem. (Upon invitation)
  • Duong MN et al. 2017. The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance. Oncotarget
  • Clement E et al. 2017. Obesity and melanoma: could fat be fueling malignancy? Pigment Cell Melanoma Research. (Upon invitation)
  • Laurent V et al. 2016. Dissemination of prostate cancer: a way paved of fat. Med Sci (Paris). (In French, invited review) 
  • Muller C et al. 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). (Invited contribution) 
  • Wang YY et al. 2012. Adipose tissue and epithelial cancer cells: a dangerous dynamic duo in breast cancer. Cancer Lett. (Upon invitation)


Role of tumor surrounding adipocytes in breast cancer progression: new links between obesity and cancer 

  • Lehuédé C*, Li X*, et al. 2019. Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP) Breast Cancer Res
  • Wang YY et al. 2017. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight. 
  • Vaysse C et al. 2017. Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer. NPJ Breast Cancer. 
  • Bochet L et al. 2013. Adipocyte-Derived Fibroblasts promote tumor progression and contribute to desmoplastic reaction in breast cancer. Cancer Res
  • Dirat B et al. 2011. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. National Press Release. Top 1 % Web of science.

 

Dissemination of prostate cancer: a way paved of fat 

 

Adipocyte exosomes promote tumor aggressiveness

 

Collaborations

Research Labs 

  • Pr Philippe VALET, Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U858, TOULOUSE, FRANCE 
  • Dr Anne Bouloumié, 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

  • For our prostate cancer topic, 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).

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

  • For our breast cancer topic, a collaboration has been established with Pr Inger THUNE’s team (Division for Cancer, Surgery and Transplantation, Department of Cancer Treatment / Translational Research on Energetics and Cancer, Ulleval University Hospital, Oslo, Norway).

We are involved in the clinical trial EBBA-II for the analysis of CLS in connection with our work on the adipose tissue characterization.
 

Grants

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M2R : FRM for Lucyle Orgerit
PhD : Ligue then ARC for Emily Clément
Post-doc : Fondation de France for Camille Attané ; FRM for David Estève