Il-6/Stat3-Mediated Inflammatory Signaling Results In Dysregulated Fibroblast Growth Factor Receptor Activation And Tumor Cell Signaling In Human Pancreatic Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by delayed diagnosis and the lowest five-year survival amongst all cancer sites. PDAC development and progression are attributed to chronic inflammation and associated tissue repair mechanisms which contribute to high density tumor formation and chemoresistance. PDAC-associated inflammation is, in part, owed to high levels of interleukin 6 (IL-6) and its activated pathways including JAK/STAT3. In Addition, Fibroblast growth factor (FGF) signaling pathways are known to be dysregulated in cancer and have been implicated in various malignancies including PDAC. As such, we sought to explore the association between IL-6-induced inflammatory signaling and FGF signaling activation. To observe this effect as it pertains to carcinogenesis and cancer progression we used four human cell lines ranging from healthy pancreatic ductal epithelial (HPDE) cells to various grade (G) PDAC cells. Cells were treated with IL-6 at a concentration of 100 ng/mL for 24 hours. The results showed increased phosphorylation of STAT3 in BxPC-3 (G2) and PANC-1 (G3) cells with no change noted in HPDE and SW1990 (G2, metastatic) cells. IL-6 stimulation likewise resulted in markedly increased phosphorylation of the fibroblast growth factor receptor substrate 2-alpha (FRS2-α) and its downstream component Erk1/2 in BxPC3 cells, indicating activation of FGF signaling through the MAPK/Erk pathway in our low grade PDAC cell model. In conclusion, the results demonstrate a potential link between IL-6 induced inflammatory signaling and dysregulation of FGF signaling in human PDAC. Activated STAT3 signaling seems to be involved in this process. Existing cancer therapies aimed at controlling growth factor signaling broadly target vascular endothelial or epithelial growth factor receptors (VEGF/EGFR) with marginal efficacy and adverse side effects in PDAC. Identifying the pivotal link between inflammatory signaling and dysregulation of fibroblast growth factor signaling will allow for the development of more precisely targeted and effective cancer therapy in pancreatic cancer. This may minimize clinically observed exaggerated fibrotic events within the tumor and may hence result in higher vulnerability for established chemotoxic therapies in the tumor cells. Citation Format: Karol Nawalaniec, Yuxiang Wang, Romana Moench, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser. IL-6/STAT3-mediated inflammatory signaling results in dysregulated fibroblast growth factor receptor activation and tumor cell signaling in human pancreatic 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 992.