TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells

• Published in: Nature communications Vol. 11; no. 1; p. 454
• Main Authors: Corbet, Cyril, Bastien, Estelle, Santiago de Jesus, Joao Pedro, Dierge, Emeline, Martherus, Ruben, Vander Linden, Catherine, Doix, Bastien, Degavre, Charline, Guilbaud, Céline, Petit, Laurenne, Michiels, Carine, Dessy, Chantal, Larondelle, Yvan, Feron, Olivier
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.01.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Acetyl Coenzyme A - metabolism; Acetylation; Acidosis; Acidosis - metabolism; Acidosis - pathology; Animals; Anoikis; Autocrine signalling; Cancer; CD36 antigen; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Droplets; Energy storage; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - physiology; Fatty acids; Female; Gene Expression Regulation, Neoplastic; Humans; Invasiveness; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Lipid Droplets - drug effects; Lipid Droplets - metabolism; Lipids; Mesenchyme; Metabolism; Metastases; Metastasis; Mice; pH effects; Phenotypes; Protein kinase C; Smad2 protein; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta2 - genetics; Transforming Growth Factor beta2 - metabolism; Transforming Growth Factor beta2 - pharmacology; Translocation; Triglycerides; Tumor microenvironment; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14262-3

Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-β2 isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-β2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-β2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-β2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited.