biostudies-literatureGomes APEuropean Research CouncilNIA NIH HHSNCI NIH HHS435-443https://www.ebi.ac.uk/biostudies/studies/S-EPMC9050834biostudies-literatureUnknown4(4)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 coenzyme A epimerase (MCEE), mediated by an extracellular signal-regulated kinase 2-driven transcription factor Sp1/early growth response protein 1 transcriptional switch driven by metastatic signalling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and intracellular and intratumoral accumulation of methylmalonic acid, a by-product of propionate metabolism that promotes cancer cellNature metabolismAltered propionate metabolism contributes to tumour progression and aggressiveness.PMC9050834F31 CA220750R35 CA197588R00 CA218686DP2 AG077698R01 CA046595711486P01 CA120964Drapela SBlenis JSchild TIlter DFendt SMLow VElia IMutvei APNunes JBMullarky ERosenzweig ANagiec MSchaffer BEGomes APAsara JMCantley LCHan JBroekaert DfalseAltered propionate metabolism contributes to tumour progression and aggressiveness.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 coenzyme A epimerase (MCEE), mediated by an extracellular signal-regulated kinase 2-driven transcription factor Sp1/early growth response protein 1 transcriptional switch driven by metastatic signalling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and intracellular and intratumoral accumulation of methylmalonic acid, a by-product of propionate metabolism that promotes cancer cell2022-01-01T00:00:00Z2022 Apr2025-05-18T12:50:04.805Z2025-02-19T03:24:14.321ZS-EPMC90508343536195410.1038/s42255-022-00553-5