Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis

Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulf-oxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancre-atic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetra-meric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.

Automated summary

Loss of MSRA, a suppressor of PDA metastasis, leads to the oxidation of methionine residue M239 in PKM2, promoting migration and metastasis of tumor cells.