SRSF12 deficiency enhances tumor innervation and accelerates pancreatic tumorigenesis

Abstract

The peripheral nervous system significantly determines the fate of solid tumors and their microenvironment. In neurotropic malignancies such as pancreatic and prostate cancer, denervation in animal models demonstrate significantly delays in tumor initiation and progression, underscoring the critical neural dependency of these cancers. While tumor innervation establishes a structural basis for the neuromodulatory effects, the degree of innervation exhibits marked heterogeneity across tumor types, and its regulatory mechanisms remain poorly characterized. In this study, we screened genes associated with innervation status in pancreatic cancer and identified the splicing factor SRSF12 as a critical gene related to tumor innervation. In clinical samples, SRSF12 was expressed at low levels in pancreatic cancer tissues, and its downregulation was linked to poor prognosis in patients. Then we crossed Kras mutation and Srsf12 knockout mice (Kras^G12D Srsf12 ^fl/fl) together with Srsf12 ^fl/fl Pdx1^cre mice and found that depletion of Srsf12 accelerated Kras-driven pancreatic tumorigenesis and enhanced tumor innervation. Furthermore, we demonstrated that SRSF12 inhibits neurite outgrowth primarily by generating a LAMA3 splice isoform that lacks the fourth and fifth LG (G45) domains. Mechanistically, G45 promotes tumor innervation by activating ITGB1 and FAK in neurons. Together, our findings delineate SRSF12 as a novel suppressor of tumor innervation and pancreatic tumorigenesis, while also identifying a tumor-specific target for SRSF12-deficient pancreatic cancer.