Abstract 4494: HMGA1 drives tumor progression and recruits cancer-associated fibroblasts in pancreatic ductal adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors for which there are no effective therapies. Emerging evidence suggests that the tumor stroma interacts with the cancer cells to induce cancer stem cell properties and drive tumor progression. In PDAC, the fibroblast stroma also provides a dense barrier preventing cytotoxic therapy from reaching PDAC cells. We previously discovered that high levels of High Mobility Group A1 (HMGA1) protein predict decreased survival in primary PDAC. Here, we report a novel role for HMGA1-FGF19 in mediating tumor-stromal interactions and tumor progression. Silencing HMGA1 in PDAC cell lines or low-passge, patient-derived cells abruptly halts proliferation. Spindle-shaped, mesenchymal cells became reprogrammed into cuboidal, more epithelial-like cells. Sensitivity to gemcitabine was enhanced and colony formation, migration, invasion, and three-dimensional (3D) sphere formation were all disrupted in cells with HMGA1 knock-down. Silencing HMGA1 also disrupted xenograft tumorigenesis and depleted cancer stem cells/tumor-initiator cells in limiting dilution tumorigenicity assays. To elucidate underlying molecular mechanisms mediating these striking phenotypes, we performed RNA-seq after silencing HMGA1 in invasive, highly metastatic, low-passage patient-derived PDAC cells (10.7). Among the genes regulated by HMGA1 were those encoding proteins involved in tumor-stromal signaling, including the fibroblast growth factor 19 (FGF19). The FGF19 gene is highly expressed in GI tumors (liver, colon, PDAC) and transgenic mice overexpressing Fgr15 (the murine homolog) in hepatocytes develop hepatocellular carcinoma (HCC). FGF19 also correlates with poor outcomes in human HCC and colon cancer, although it's role in PDAC was unknown. Here, we found that FGF19 expression is dependent upon HMGA1 in 3 different PDAC cell lines; silencing HMGA1 represses FGF19 in these cells. HMGA1 also binds directly to the FGF19 promoter at 2 predicted DNA binding sites as assessed by chromatin immunoprecipiation. To determine whether FGF19 plays a functional role in HMGA1-mediated tumor progression and cancer stem cell properties, we silenced FGF19 in PDAC cells. Similar to our results with HMGA1, silencing FGF19 impaired PDAC growth and 3D sphere formation in vitro. Because fibroblast growth factors interact with fibroblasts, we determined whether the HMGA1-FGF19 pathway was involved in tumor cell – stromal crosstalk. PDAC 10.7 cells recruit cancer-associated fibroblasts (CAFs) in a co-culture system, although this recruitment was abrogated when HMGA1 was silenced. CAF migration was also disrupted by anti-human FGF19 neutralizing antibodies. Together, these findings indicate that HMGA1 drive tumor progression and cancer stem cell properties through FGF19 and suggest that targeting the HMGA1-FGF19 pathway maybe efficaceous in PDAC. Citation Format: Shuai Shuai, Lingling Xian, Tait Huso, Karen Reddy, Linda Resar. HMGA1 drives tumor progression and recruits cancer-associated fibroblasts in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4494.