Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition

作者：Xiuhui Shi, Min Wang, Yuqing Zhang, Xingjun Guo, Mingyang Liu, Zhijun Zhou, Yan Zhao, Ruizhi He, Yang Gao, Yuhui Liu, Shutao Pan, Min Zhou, Chunle Zhao, Taoyuan Yin, Xu Li, Hebin Wang, Jingxuan Yang, Feng Zhu, Min Li, Renyi Qin · 发表于：EBioMedicine · 年份：2022 · DOI：10.1016/j.ebiom.2022.104352 · 被引用次数：35 · 研究领域：Cancer, Hypoxia, and Metabolism、Liver physiology and pathology、Cancer Cells and Metastasis

BACKGROUND: Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). METHODS: The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. FINDINGS: We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppress...