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Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells
Yuan Yuan Wang, … , Philippe Valet, Catherine Muller
Yuan Yuan Wang, … , Philippe Valet, Catherine Muller
Published February 23, 2017
Citation Information: JCI Insight. 2017;2(4):e87489. https://doi.org/10.1172/jci.insight.87489.
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Research Article Oncology

Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells

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Abstract

In breast cancer, a key feature of peritumoral adipocytes is their loss of lipid content observed both in vitro and in human tumors. The free fatty acids (FFAs), released by adipocytes after lipolysis induced by tumor secretions, are transferred and stored in tumor cells as triglycerides in lipid droplets. In tumor cell lines, we demonstrate that FFAs can be released over time from lipid droplets through an adipose triglyceride lipase–dependent (ATGL-dependent) lipolytic pathway. In vivo, ATGL is expressed in human tumors where its expression correlates with tumor aggressiveness and is upregulated by contact with adipocytes. The released FFAs are then used for fatty acid β-oxidation (FAO), an active process in cancer but not normal breast epithelial cells, and regulated by coculture with adipocytes. However, in cocultivated cells, FAO is uncoupled from ATP production, leading to AMPK/acetyl-CoA carboxylase activation, a circle that maintains this state of metabolic remodeling. The increased invasive capacities of tumor cells induced by coculture are completely abrogated by inhibition of the coupled ATGL-dependent lipolysis/FAO pathways. These results show a complex metabolic symbiosis between tumor-surrounding adipocytes and cancer cells that stimulate their invasiveness, highlighting ATGL as a potential therapeutic target to impede breast cancer progression.

Authors

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, Catherine Muller

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Figure 2

In the presence of adipocytes, breast cancer cells undergo a metabolic switch toward uncoupled mitochondrial fatty acid oxidation (FAO).

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In the presence of adipocytes, breast cancer cells undergo a metabolic s...
ZR-75-1 cells were cocultivated (C) or not (NC) with adipocytes for 3 days. (A) Lipid accumulation in tumor cells in the presence (+E) or not of Etomoxir (1 μM and 30 μM). Left, triglycerides (TG) content (n = 6). Right, lipid staining with Bodipy in green and DAPI in blue. Etomoxir (30 μM). Scale bars: 30μm. (B) Expression of the indicated genes measured by qPCR in tumor cells (n = 4). (C) Mitochondrial DNA (ratio of mitochondrial [mtDNA] to genomic [gDNA] DNA levels) levels in tumor cells (n = 3). (D) Representative experiments of transmission electron microscopy highlighting mitochondrial ultra-structural changes (*) in C or NC. Scale bars: 1 μm and 2 μm. (A and D) At least 3 experiments were conducted, and representative images are shown. (E) Total ATP production in tumor cells (n = 4). (F) ATP generated by glycolysis in tumor cells (n = 4). (G) Lactate released by tumor cells (n = 6). (H) Extracellular acidification rate (ECAR) evaluated after addition of 10 mM glucose to tumor cells (n = 12). (I) Oxygen consumption rate (OCR) was measured in the presence of palmitate and coupled respiration, proton leak and nonmitochondrial respiration were calculated as described in Methods (n = 9–12). Bars and error flags represent means ± SEM; statistically significant by Mann-Whitney U test (A, B and I) or Student’s t test (C–H), *P < 0.05, **P < 0.01, ***P < 0.001.

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