Abstract C070: Investigation of the roles of BDKRB1 in pancreatic cancer progression and tumor microenvironment modulation

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with features of early metastasis and extensive desmoplasia which is the growth of fibrous or connective tissue. The PDAC patient outcomes have not improved in decades, albeit a plenty of therapies that target PDAC have been tested but failed. It could be due to most research focused on tumor cells, whereas the effect of the stroma and immune cells during tumor progression has been largely ignored. Bradykinin receptor B1 (BDKRB1), one of the cell-surface G protein-coupled receptors plays a crucial role in the physiological process associated with coagulation, vasodilation and promotes fibrotic diseases and inflammation in pathological conditions. Based on the analyzed results of Cancer Genome Atlas (TCGA) database, BDKRB1 mRNA is upregulated in PDAC patients. Of note, BDKRB1 mRNA level positively associates with several activated human pancreatic stellate cells (HPSCs; the main fibroblastic cells of the pancreas)-related genes such as CTGF (connective tissue growth factor), IL6 (interleukin 6), and PDGFB (platelet derived growth factor subunit B) in PDAC patients. Interestingly, the conditioned medium from des-Arg9-bradykinin treated-HPSCs can induce M2-like macrophages polarization which dictate clinically relevant immunosuppression in metastatic tumors and express immunosuppressive cytokines such as IL-10, CCL17 and CCL18, implying that activation of BDKRB1 not only stimulates PDAC growth, but also causes HPSCs activation, desmoplasia and immune suppression, followed by exacerbating tumor progression. Moreover, a chemotherapy gemcitabine remains a cornerstone of PDAC treatment in all stages of PDAC despite of the low therapeutic efficacy, we demonstrated that treatment of gemcitabine increases the expression of BDKRB1 in HPSCs and PDAC, indicating that activation of BDKRB1 could be one of the mechanisms involved in gemcitabine resistance. Here, we hypothesize BDKRB1 activation may orchestrate the tumor microenvironment which promotes PDAC progression by inducing tumor cells survival, HPSCs activation, immune suppression, and may contribute to chemotherapy resistance. The outcomes of this proposal will provide not only a novel cellular and molecular mechanism involved in progression of PDAC, but also highlight a potential therapeutic approach to improve PDAC treatment. Citation Format: Ching-Fei Li, Jie Fu, Heng-Huan Lee, Ying-Nai Wang, Yu-Yi Chu, Paul J. Chiao, Mien-Chie Hung. Investigation of the roles of BDKRB1 in pancreatic cancer progression and tumor microenvironment modulation [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C070.