Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer

Abstract

Despite a critical role for MYC as an effector of oncogenic RAS, strategies to target MYC activity in RAS-driven cancers are lacking. Oncogenic KRAS is insufficient to drive tumorigenesis, while addition of modest overexpression of MYC drives robust tumor formation, suggesting that mechanisms beyond the RAS pathway play key roles in MYC regulation and RAS-driven tumorigenesis. Here we show that acidic fibroblast growth factor (FGF1) derived from cancer-associated fibroblasts (CAFs) cooperates with cancer cell-autonomous signals to increase MYC level, promoter occupancy, and activity. FGF1 is necessary and sufficient for paracrine regulation of MYC protein stability, signaling through AKT and GSK-3β. These signals cooperate with, but are distinct from, cell-autonomous signals from oncogenic KRAS which stabilize MYC. Human pancreatic cancer specimens reveal a strong correlation between stromal CAF content and MYC protein level in the neoplastic compartment, and identify CAFs as the specific source of FGF1 in the tumor microenvironment. Together, our findings demonstrate that MYC is coordinately regulated by cell-autonomous and microenvironmental signals, and establish CAF-derived FGF1 as a novel paracrine regulator of oncogenic transcription. Statement of significance Our work highlights an unanticipated role for the tumor microenvironment in the regulation of MYC protein stability in pancreatic cancer cells and identifies CAF-derived FGF1 as a novel, specific paracrine regulator of MYC.