Hmga1 Induces Fgf19 To Drive Tumor Progression And Recruit Cancer Associated Fibroblasts In Pancreatic Adenocarcinoma.

Abstract Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by a dense desmoplastic stroma comprised of cancer associated fibroblasts (CAFs) and fibrotic scar tissue. While stromal CAFs act as a barrier to therapy and release signals promoting tumor growth and invasion, the stroma restricts tumor growth in mouse models. The High Mobility Group A1 (HMGA1) protein is an oncofetal protein and epigenetic regulator that amplifies signals from the microenvironment to foster stem cell properties within intestinal epithelium. Although HMGA1 is highly expressed in embryonic and adult stem cells, it is silenced postnatally in most differentiated cells. HMGA1 becomes aberrantly re-expressed in diverse tumors where high levels predict adverse clinical outcomes. In PDAC, HMGA1 is detected only in late-stage precursor lesions or invasive tumors, but not in normal pancreas nor in early precursor lesions. Moreover, high HMGA1 nuclear staining associates with poor differentiation status and decreased patient survival. Here, we discovered a novel epigenetic program whereby HMGA1 recruits stromal CAFs and drives tumor progression by inducing FGF19. Silencing HMGA1 in PDAC cell lines slows proliferation, disrupts oncogenic properties in vitro (migration, invasion, clonogenicity, 3D sphere formation), and depletes tumor initiator cells in xenograft assays. RNA sequencing revealed transcriptional networks up-regulated by HMGA1 that function in cell signaling and proliferation; we focused on FGF19 as a potential mediator of tumor-stromal crosstalk. HMGA1 binds directly to the FGF19 promoter and recruits active histone marks (H3K4me2, H3K27Aac) to induce gene expression and protein secretion from PDAC cells. Silencing FGF19 recapitulates effects of HMGA1 silencing, disrupting oncogenic and cancer stem cell properties in vitro while depleting tumor initiator cells in vivo. In co-culture experiments, FGF19 is required for CAF migration across a membrane towards PDAC cells. Silencing HMGA1, FGF19, or treatment with FGF19 inhibitors disrupts CAF recruitment. Silencing HMGA1 or FGF19 in PDAC cells also decreases both the desmoplastic stroma and tumor growth in mouse xenografts. In primary tumors, co-expression of HMGA1 and FGF19 predict decreased survival. Together, our results reveal a novel paradigm whereby tumor cells collaborate with CAFs via HMGA1 and FGF19 to drive progression, thus illuminating FGF19 as a rational therapeutic target for PDACs overexpressing HMGA1 and FGF19. Citation Format: Lionel Chia, Shuai Shuai, Jung-Hyun Kim, Woo Jung Sung, Ruitao Zhang, Tait Huso, Leslie Cope, Karen Reddy, Linda M. Resar. HMGA1 induces FGF19 to drive tumor progression and recruit cancer associated fibroblasts in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2414.