Altered propionate metabolism contributes to tumour progression and aggressiveness.

Abstract

The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that dysregulation of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells, increasing their metastatic potential. This occurs through the downregulation of methylmalonyl-CoA epimerase (MCEE), mediated by an ERK2-driven SP1/EGR1 transcriptional switch driven by metastatic signaling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and the intracellular and intratumoral accumulation of methylmalonic acid (MMA), a byproduct of propionate metabolism that promotes cancer cell invasiveness. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as an important contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.