Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.

Abstract

Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet (LD) accumulation and oxidative phosphorylation, characteristics of aggressive cancers. Here, we use live imaging, shotgun lipidomics, and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FA), which are converted to triacylglycerols (TAG) and stored in LDs. Consistent with its independence of de novo synthesis, TAG- and LD accumulation in acid-adapted cells is unaffected by FA-synthetase inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributes to FA uptake, which is independent of other protein-facilitated lipid uptake mechanisms, including CD36, FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.