The lipid phosphatase INPP4B controls pancreatic cancer cell migration and invasion by regulating fibronectin exocytosis

Increased expression of Inositol Polyphosphate 4-Phosphatase, Type II (INPP4B) correlates with aggressive phenotypes in pancreatic ductal adenocarcinoma (PDAC). Although prior studies have linked INPP4B to lysosome positioning, exocytosis, and enhanced cell migration and invasion in PDAC, the specific mechanisms underlying these processes remain unclear. In this study, we demonstrate that INPP4B promotes fibronectin 1 (FN1) secretion via TRPML1-dependent lysosomal exocytosis. Additionally, we show that INPP4B-mediated regulation of F-actin formation, focal adhesion kinase (FAK) activation, and increased cell migration and invasion depend on FN1 exocytosis. These findings underscore the INPP4B-TRPML1-FN1 axis as a critical contributor to PDAC aggressiveness and identify it as a promising candidate for the development of new therapeutic strategies.