BCAT1-elicited branched-chain amino acid catabolism fosters neutrophil-mediated pan-metastasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy that disseminates via all known metastatic routes, with the underlying mechanisms poorly understood. PDAC exhibits unique immune microenvironment and distinct amino acid metabolic adaptations, but whether and how these features cooperate to drive pan-metastasis remain unclear. This study identifies a distinct population of metastasis-associated tumor cells in PDAC and uncovers branched-chain amino acid transaminase 1 (BCAT1) as a critical determinant of their metastatic potential. Clinically, elevated BCAT1 expression correlates with poor prognosis and serves as an independent risk factor in PDAC patients. Notably, although BCAT1 promotes pancreatic cancer metastasis in vivo, its overexpression in vitro fails to affect the invasive properties of the cells, highlighting the indispensable role of the tumor microenvironment. Mechanistically, BCAT1 catalyzes leucine catabolism to generate α-ketoisocaproate, leading to mammalian target of rapamycin (mTOR) pathway activation and subsequent increased production of neutrophil-recruiting chemokines. This facilitates neutrophil infiltration and fosters pro-metastatic niche in tumors. Simultaneously, mTOR pathway activation enhances tumor cell responsiveness to neutrophils, establishing a synergistic metabolic-immune loop. Targeting BCAT1 or disrupting its downstream mTOR/nuclear factor-κB signaling effectively inhibits PDAC pan-metastasis. These results uncover an unrecognized metabolic-immune crosstalk governing BCAT1+ metastasis-related tumor cells and pan-metastasis of PDAC.