A Palmitoylation Switch Controls Mitochondrial Translocation of SHP2 to Drive Metabolic Subtype Specification in Pancreatic Cancer

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is driven by its profound heterogeneity, exemplified by the aggressive basal and more indolent classical subtypes. While metabolic reprogramming underpins this heterogeneity, the upstream regulatory mechanisms remain elusive. Here, we uncover the dynamic palmitoylation cycle as a critical spatial regulator of oncogenic signaling that dictates PDAC subtype fate. We identify a depalmitoylation-dominant state in the basal subtype, orchestrated by the transcriptional upregulation of acyl-protein thioesterase 1 (APT1) via the KRAS-MYC axis. Mechanistically, APT1 directly depalmitoylates the tyrosine phosphatase SHP2 at Cys104, Cys563, and Cys569, thereby triggering its translocation from the plasma membrane to mitochondria. This spatial redistribution facilitates SHP2's interaction with DRP1, amplifying its activation to drive mitochondrial fragmentation, which is a metabolic gateway to high glycolytic flux, redox balance, and enhanced lipid utilization that sustains the basal subtype. Conversely, the palmitoyltransferase ZDHHC7 anchors SHP2 at the membrane, a feature enriched in classical PDAC. Notably, inhibiting APT1 with ML348 forces SHP2 membrane retention, disrupts mitochondrial plasticity, reverses basal differentiation, and suppresses tumor growth. Our findings reveal a novel palmitoylation switch that spatially controls SHP2 to govern metabolic heterogeneity, proposing depalmitoylation inhibition as a promising therapeutic target for aggressive PDAC.