title: Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells.
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.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.|Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPS, Toulouse, France.|Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPS, Toulouse, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Attané
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.
authors.forename: Delphine
authors.initials: D
authors.lastname: Milhas
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.|Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPS, Toulouse, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Dirat
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dauvillier
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.
authors.forename: Adrien
authors.initials: A
authors.lastname: Guerard
authors.affiliation: Departement de Biostatistiques, Institut Universitaire du Cancer, Toulouse, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Gilhodes
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.
authors.forename: Ikrame
authors.initials: I
authors.lastname: Lazar
authors.affiliation: EVOTEC France, Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Alet
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.
authors.forename: Victor
authors.initials: V
authors.lastname: Laurent
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPS, Toulouse, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Gonidec
authors.affiliation: CEA, DSV, IMETI/SEPIA, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Biard
authors.affiliation: EVOTEC France, Toulouse, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hervé
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1065, Centre Méditerranéen de Médecine Moléculaire, Nice, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bost
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Guo Sheng
authors.initials: GS
authors.lastname: Ren
authors.affiliation: EVOTEC France, Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bono
authors.affiliation: Service d'Anatomo-Pathologie, Institut Universitaire du Cancer, Toulouse, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Escourrou
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.
authors.forename: Laurence
authors.initials: L
authors.lastname: Nieto
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPS, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS.
authors.forename: Catherine
authors.initials: C
authors.lastname: Muller
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D008066:Lipolysis; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D000103:Acetyl-CoA Carboxylase; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D005230:Fatty Acids, Nonesterified; D008049:Lipase; D014280:Triglycerides; C494794:PNPLA2 protein, human; D000217:Acyltransferases