Breast cancer remains the leading cause of death by cancer in the world, due to the dissemination of tumor cells leading to metastasis. Pr Catherine Muller-Staumont’s team showed that fat cells or adipocytes, abundant in breast tissue, transfer lipids to tumor cells supporting their dissemination. Cancer cells store these lipids and release them over time to maintain an aggressive phenotype after their initial contact with adipocytes. These results were published in JCI Insight on 23rd February 2017.
Breast cancer is the most frequent women’s cancer. Despite advances in the characterization and the treatment of the disease, breast cancer remains the leading cause of death by cancer in the world, due to local and distant dissemination of tumor cells and subsequent metastasis formation. Fat cells or adipocytes are in close proximity to breast cancer cells and the team has already shown that a crosstalk takes place between cancer cells and adipocytes at the invasive front of tumors (where the tumor comes into contact with the surrounding adipose tissue) (Dirat et al. Cancer Research, 2011 ; Bochet et al. Cancer Research 2013). As tumor-surrounding adipocytes exhibit a decreased size and lipid content, researchers investigated whether cancer cells could capture and use the lipids released by these adipocytes.
Researchers showed that, when co-cultivated with cancer cells, adipocytes release lipids (fatty acids) which are captured and stored in lipid droplets in tumor cells. These results were confirmed at the invasive front of breast tumors from patients. Upon lipid uptake, cancer cells modify their metabolism to use these fatty acids as a new energy supply, favoring their invasive capacities. Pharmacological and genetic inhibition of this metabolic remodeling (to block fatty acid transfer to mitochondria, the cellular organelle in which lipids are metabolized) impair the invasive capacities of tumor cells co-cultivated with adipocytes in vitro but also reduce the number and size of pulmonary metastasis in mice models in vivo.
Moreover, they studied whether tumor cells can release the excess lipids that they store as triglycerides (fatty acid polymers) within lipid droplets. This process allows cancer cells to have a constant energy source, even when they are no longer in direct contact with adipocytes after leaving the primary tumor and entering the bloodstream to reach the metastatic site. Catherine Muller’s team showed that cancer cells mobilize triglycerides via the enzymatic activity of ATGL (Adipose TriGlyceride Lipase) and demonstrated, for the first time, that this enzyme is expressed in breast cancer cells. ATGL is upregulated in aggressive tumor cell lines and in tumor cells cocultivated with adipocytes in vitro. ATGL inhibition blocks fatty acid release and use, thus preventing the increased tumor cell invasion induced by coculture with adipocytes. In human tumors, ATGL expression correlates with tumor aggressiveness and is increased at the invasive front.
Overall, this work shows that a metabolic symbiosis exists between adipocytes and cancer cells through a direct lipid transfer, which is an important step in breast cancer cell dissemination. These results reveal that blocking lipid mobilization and use (ie: inhibition of fatty acid release from lipid droplets and their transport to the mitochondria) represent new therapeutic targets for the treatment of breast cancer. These targets could be even more relevant for obese patients who present more aggressive tumors with surrounding adipocytes that contain more lipids.
 This work was performed in collaboration with the group of Philippe Valet at the Institute of Cardiovascular and Metabolic Diseases (Inserm/Université Toulouse III – Paul Sabatier) and the Anatomo-Pathology department of the University Cancer Institute Toulouse and was funded by the ‘Institut National du Cancer’, ‘Ligue contre le cancer’ (Midi-Pyrénées) and ‘Fondation de France’.
Figure legend: Under the effect of tumor secretions, adipocytes at the invasive front of breast tumors release their lipids, which will be then captured and stored as lipid droplets by cancer cells. The tumor cells will release these lipids over time via the enzymatic activity of ATGL, and use them as a source of energy, which will allow tumor cells to increase their invasive capacities. © Catherine Muller
Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells
Yuan Yuan Wang, Camille Attané, Delphine Milhas, Béatrice Dirat, Stéphanie Dauvillier, Adrien Guerard, Julia Gilhodes, Ikrame Lazar, Nathalie Alet, Victor Laurent, Sophie Le Gonidec, Denis Biard, Caroline Hervé, Frédéric Bost, Guo Sheng Ren, Françoise Bono, Ghislaine Escourrou, Marc Prentki, Laurence Nieto, Philippe Valet, and Catherine Muller. JCI Insight 2017 2(4):e87489 doi:10.1172/jci.insight.87489
Principal investigator IPBS l Pr. Catherine MULLER l Catherine.Muller@ipbs.fr
Press contact IPBS l Francoise VIALA l Communication@ipbs.fr | +33 601 265 259
Read the Press Release on the INSB website (in french)