Hmga1 Induces Fgf-19 To Foster Tumor-Stromal Cell Crosstalk And Drive Tumor Progression In Pancreatic Ductal Adenocarcinoma

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 provide a barrier to therapy and release signals that foster tumor growth and invasion, the stroma also restrains tumor growth in murine models. The High Mobility Group A1 (HMGA1) chromatin remodeling gene encodes an oncofetal protein and epigenetic regulator that amplifies signals from the microenvironment to foster stem cell properties within intestinal epithelium. HMGA1 is also highly expressed during embryogenesis and in adult stem cells, but silenced postnatally in most differentiated cells. In diverse, aggressive cancers, HMGA1 becomes aberrantly re-expressed where high levels portend adverse clinical outcomes. In PDAC, HMGA1 protein is detected in late stage precursor lesions and invasive tumors, but not in normal pancreas nor in early precursor lesions. Furthermore, high HMGA1 levels correlate with poor differentiation status and decreased patient survival. Here, we discovered a novel epigenetic program mediated by HMGA1 that recruits CAFs to drive PDAC progression. We discovered that silencing HMGA1 in multiple PDAC cell lines halts proliferation and disrupts oncogenic properties, including migration, invasion, clonogenicity, and xenograft tumorigenesis. HMGA1 silencing also impairs three-dimensional sphere formation and depletes tumor initiator cells in limiting dilution assays. Through RNA sequencing analysis comparing PDAC cells overexpressing HMGA1 to those with HMGA1 silencing, we identified FGF-19 as a potential transcriptional target of HMGA1. HMGA1 binds specifically to the FGF-19 promoter and recruits the active histone mark, H3K4me3, to activate its expression. HMGA1 is also required for FGF-19 secretion from PDAC cells. Similar to HMGA1, silencing FGF-19 blocks oncogenic and cancer stem cell properties in vitro while disrupting tumorigenesis and depleting tumor initiator cells in vivo. In co-culture experiments, HMGA1 expressed in PDAC cells amplifies FGF-19 secretion, thereby stimulating CAF migration to tumor cells across a membrane. Silencing HMGA1 or FGF-19 prevents CAF recruitment to PDAC tumor cells. Furthermore, CAF recruitment is blocked by either FGF-19 blocking antibodies or an inhibitor to the FGF-19 receptor (FGR4). In murine models, silencing HMGA1 also decreases formation of a fibroblastic stroma. Moreover, overexpression of HMGA1 together with that of FGF-19 predict decreased survival in primary human PDAC. Our results reveal a novel paradigm whereby PDAC cells collaborate with stromal CAFs via HMGA1 and FGF-19 to drive tumor progression. These data also provide insight into mechanisms for tumor progression and illuminate FGF-19 as a rational therapeutic target in PDACs with up-regulation of HMGA1 and FGF-19. Citation Format: Lionel Chia, Shuai Shuai, Lingling Xian, Jung-Hyun Kim, Ruitao Zhang, Tait Huso, David Huso, Leslie Cope, Karen Reddy, Linda Resar. HMGA1 induces FGF-19 to foster tumor-stromal cell crosstalk and drive tumor progression in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 297.