Chronic acidosis rewires cancer cell metabolism through PPARα signaling

The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH( e )) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH( e ), but not at acidic pH( e ). Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation‐induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet‐, triacylglycerol‐, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator‐activated receptor‐α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β‐oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin‐interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid‐adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid‐adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.