The role of Sorting nexin 10 (SNX10) as a tumor suppressor in pancreatic ductal adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of pancreatic cancer, ranking as the third leading cause of cancer-related deaths in the United States. Despite its clinical significance, the molecular mechanisms driving PDAC development and progression remain poorly understood. In this study, we investigate the role of Sorting nexin 10 (SNX10), a member of the sorting nexin family, in PDAC pathogenesis. SNX10 is known to regulate intracellular vesicular cargo transport and signaling, but its function in pancreatic cancer has not been well characterized. Our analysis of human PDAC tissues revealed that SNX10 expression is significantly downregulated compared to normal pancreatic tissues. Furthermore, mutational analysis identified SNX10 alterations in multiple PDAC samples, with a significant proportion co-occurring with KRAS gain of function (GOF) mutations. Functional studies demonstrated that SNX10 overexpression in human PDAC cells suppresses tumorigenic properties, including cell proliferation, colony formation, and migration, while also inducing G1-phase cell cycle arrest and inhibiting the phosphorylation of key pro-tumorigenic proteins. To further explore the physiological role of SNX10 in PDAC, we developed a novel Snx10 knockout PDAC mouse model. Loss of Snx10 in these mice resulted in reduced survival, increased tumor cell proliferation, heightened tumor aggressiveness, increased inflammation, and upregulated expression of pro-tumorigenic markers. Collectively, our findings suggest that SNX10 functions as a tumor suppressor in PDAC. These results highlight SNX10 as a potential diagnostic biomarker and therapeutic target in this highly aggressive malignancy.