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

Cyril Corbet, Estelle Bastien, Joao Pedro Santiago de Jesus, Emeline Dierge, Ruben Martherus, Catherine Vander Linden, Bastien Doix, Charline Degavre, Céline Guilbaud, Laurenne Petit, Carine Michiels, Chantal Dessy, Yvan Larondelle, Olivier Feron

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number454
Pages (from-to)454
Number of pages15
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 23 Jan 2020
Externally publishedYes

Keywords

  • Acetyl Coenzyme A/metabolism
  • Acidosis/metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • Colorectal Neoplasms/genetics
  • Epithelial-Mesenchymal Transition/drug effects
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms/genetics
  • Lipid Droplets/drug effects
  • Mice
  • Transforming Growth Factor beta1/metabolism
  • Transforming Growth Factor beta2/genetics
  • Xenograft Model Antitumor Assays

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  • Equipment

    Morphology - Imaging

    Charles Nicaise (Manager) & Francesca Cecchet (Manager)

    Technological Platform Morphology - Imaging

    Facility/equipment: Technological Platform

  • Cite this

    Corbet, C., Bastien, E., Santiago de Jesus, J. P., Dierge, E., Martherus, R., Vander Linden, C., Doix, B., Degavre, C., Guilbaud, C., Petit, L., Michiels, C., Dessy, C., Larondelle, Y., & Feron, O. (2020). TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells. Nature Communications, 11(1), 454. [454]. https://doi.org/10.1038/s41467-019-14262-3