TGF-β2 at the crossroads between tumor acidosis, lipid metabolism and epithelial-to-mesenchymal transition
(2020)
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- Cancer progression is strongly influenced by the physico-chemical properties of the tumor microenvironment. In particular, tumor cells must adapt to survive and proliferate not only under low pO2 (hypoxia) but also low pH (acidosis). Indeed, extracellular pH in tumors is about 10-fold more acidic than in healthy tissues, with mean values ranging from 6.2 to 6.8. While tumor acidosis has been already reported to promote cancer cell invasion, evasion to immune system, drug resistance and metastatic dissemination, little is known about its influence on the metabolic preferences in cancer cells. Here, we demonstrate that cancer cells chronically exposed to acidosis (pH 6.5) exhibit a dysregulated fatty acid (FA) metabolism with the concomitance of mitochondrial FA oxidation (FAO) and cytosolic glutamine-fueled FA synthesis (FAS). This is enabled due to a downregulation of acetyl-CoA carboxylase ACC2 making mitochondrial fatty acyl-CoA degradation compatible with cytosolic lipogenesis. Perturbations of these regulatory processes lead to tumor growth inhibitory effects further identifying FA metabolism as a critical determinant of tumor cell proliferation under acidosis. We also report that TGF-β2 is at the interface between these metabolic alterations and progression of tumor disease. 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. Acidosis-induced TGF-β2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism. We have shown 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 activity or oxidized to generate ATP to fulfill immediate cellular needs. We also document how, by preventing fatty acid mobilization from LD, distant metastatic spreading can be inhibited. Finally, we provide experimental evidence documenting how TGF-β2 is activated in acidosis-adapted cancer cells. We identify an upregulation of thrombospondin 1 (TSP-1), under chronic acidosis, that can bind to latent TGF-β2 and convert it to its biologically active form, through a non-proteolytic mechanism. Moreover, TGF-β2-dependent translocation of CD36, a fatty acid transporter, works as an “anchor” for TSP-1 at the cell membrane. Indeed, we show that CD36 is expressed in lipid rafts at the surface of acidosis-adapted cancer cells, where it co-localizes with TGF-β receptors. This leads to a local effect of TGF-β-signaling that promotes RhoA degradation and consequent cytoskeleton remodeling needed for lamellipodia formation and cell migration. In conclusion, the work presented in this PhD thesis, points out fatty acid metabolism and TGF-β2 signaling as key drivers of the aggressiveness of cancer cells exposed to chronic acidosis. Our results also open new therapeutic perspectives with the validation of strategies interfering with these processes to prevent metastatic dissemination in mouse models.
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Santiago de Jesus, J. P. (2020). TGF-β2 at the crossroads between tumor acidosis, lipid metabolism and epithelial-to-mesenchymal transition. https://hdl.handle.net/2078.5/117159