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Deciphering the role of adipose tissue in breast cancer progression and regulation by obesity

Breast cancer is the most common cancer in women worldwide. Women with breast cancer who are overweight or obese have a shorter disease-free survival, a higher mortality and a decreased response to chemotherapy, relative to their lean counterparts.

 

Mammary adipose tissue (MAT) is a major component of the breast tumor microenvironment. Our team has been among the first to characterize the modifications of tumor surrounding adipocytes. We named them CAAs for Cancer-Associated adipocytes, a term that is now widely used by the international community (Fig. 1). CAAs  exhibit a decrease in size and lipid content and an activated phenotype marked by an increase expression of pro-inflammatory cytokines and proteins involved in the extra-cellular matrix (ECM) remodeling (Dirat et al, Cancer Research, 2011, 500 citations in Web of Science, Top 1%). Upon prolonged exposure to cancer cells, adipocytes will dedifferentiate into fibroblasts and as such represents a sub-population of the Cancer-Associated Fibroblasts (CAFs) (Bochet et al, Cancer Research, 2013, Top 1 % Web of Science). Initially identified by our team in breast cancer, it is now widely acknowledged, in all solid tumors, that the invasion of proximal adipose tissue leads to profound delipidation of adipocytes, that could ultimately lead to the accumulation of fibroblast- like cells. In turns, CAAs promote cancer aggressiveness (especially the invasive capacities of cancer cells) and resistance to conventional chemotherapy through their abilities to secrete different soluble factors including interleukin 6 (Dirat et al, Cancer Research, 2011; Bochet et al, Cancer Research, 2013 : Lehuédé et al, Breast Cancer Research, 2019 ; for review, Duong et al, Oncotarget, 2017).

 

One of the most specific and emerging mechanism regarding the role of mature adipocytes in the tumor microenvironment involves the ability of cancer cells to advantageously exploit the nourishing role of adipocytes. In breast cancer, we have demonstrated that tumor cells induce lipolysis in adipocytes leading to the release free fatty acid (FFA) that are taken up by tumor cells. These FFA trigger a complex metabolic remodeling in cancer cells (see Figure 2) increasing their invasive and metastatic abilities (Wang et al, JCI insight, Top 1% Web of Science). Again, this metabolic crosstalk has now been demonstrated in a wide range of models such as ovarian, colon and prostate cancers as well as melanoma, and we have recently highlighted the importance of this concept in a review (Attané and Muller, Trends in Cancer, 2020).

 

 

Our current hypothesis is that this metabolic symbiosis is amplified in obesity. In fact, we have shown in collaboration with the group of Inger Thune in Oslo that mammary adipocytes exhibit increased size and lipid content in obese as compared to lean patients (Vaysse et al, Npj Breast Cancer, 2017). In collaboration with the pathologists and surgeons of the Toulouse Cancer Institute, we have set a new program to explore this hypothesis in vitro and in vivo.

 

Principal investigators :

Frédérique Fallone, Charlotte Vaysse and Catherine Muller


Other staff involved:
Stéphanie Dauvillier (Engineer), Marie Rebeaud (PhD student, Fellow of the Ligue contre le Cancer), Caroline Bouche (Breast Cancer surgeon, resident, Research Master)

 

Selected publications :

  • Dirat B et al. 2011 Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res (Top 1% Web of Science)
  • Bochet L et al. 2011 Cancer-associated adipocytes promotes breast tumor radioresistance. Biochem Biophys Res Commun
  • Bochet L et al. 2013 Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res (Top 1% Web of Science)
  • Vaysse C et al. 2017 Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer. NPJ Breast Cancer
  • Wang YY et al. 2017. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight (Top 1% Web of Science)
  • Fallone F et al. 2018 Breast cancer, obesity and adipose tissue: a high-risk combination. Med Sci (Paris)
  • 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

 

Collaborators :

Dr Anne Bouloumié’s group, Institute of Metabolic and Cardiovascular diseases (I2MC), Toulouse
Pr Philippe Valet’s group, RESTORE Institute, Toulouse
Dr Camille Franchet, Pathology Department of the University Toulouse Cancer center (headed by Pr P. Brousset)

Pr Olivier Piot’group, Translational BioSpectroscopy, Reims

Dr Inger Thune, Translational Research on Energetics and Cancers department, Ulleval University Hospital, Oslo, Norway (visit the Thune webpage : http://ous-research.no/trec/)