Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis

Abstract

The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH3. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.