The role of the High Mobility Group A1 Proteins in Pancreatic Cancer and Desmoplasia

Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma with cancer-associated fibroblasts (CAFs). However, the role of CAFs in tumor progression is controversial; CAFs release signals stimulating tumor growth, whereas they restrain tumor growth in murine models. The High Mobility Group A1 (HMGA1) gene encodes an oncofetal protein and chromatin regulator that is up-regulated in PDAC where high levels portend adverse outcomes. Here, we discovered a novel epigenetic program whereby HMGA1 recruits CAFs to drive tumor progression. Silencing HMGA1 disrupts multiple oncogenic properties (proliferation, clonogenicity, migration, invasion, 3D sphere formation, xenograft tumorigenesis) and depletes tumor-initiator cells in limiting dilution tumor assays. RNA sequencing revealed the FGF19 gene among transcriptional networks regulated by HMGA1 that drive cell cycle progression and tumor-stromal interactions. HMGA1 directly binds to the FGF19 promoter and recruits active histone marks (H3K4me3, H3K27Ac) to induce FGF19 expression and secretion from PDAC cells. Silencing FGF19 disrupts HMGA1-mediated oncogenic and cancer stem cell properties. In co-culture experiments, FGF19 is required for CAF migration towards PDAC cells. Silencing HMGA1, FGF19, or FGF19 inhibitors prevent CAF recruitment to PDAC cells in vitro whereas HMGA1 or FGF19 deficiency decreases desmoplastic stroma formation in xenograft tumors. Hmga1 deficiency in transgenic mouse model of PDAC delays tumor formation. In primary PDAC, high expression of HMGA1 and FGF19 predict decreased survival. Together, our results reveal a new paradigm whereby cancer cells collaborate with CAFs via HMGA1-FGF19 to drive progression, thus illuminating FGF19 as a rational therapeutic target for a subset of PDACs