AR通路抑制剂诱导成骨细胞分泌的ECM1激活Wnt信号促进骨转移前列腺癌治疗抵抗机制研究

内分泌治疗是骨转移前列腺癌（PCa）一线方案。但绝大部分患者最终耐药，转归为去势抵抗骨转移PCa，成为其主要死因，耐药机制有待阐明。前期研究证实，成骨细胞壁龛是决定骨转移PCa预后的关键之一，可能在诱导PCa治疗抵抗中起重要作用。预实验发现，雄激素受体通路抑制剂（ARPIs）恩杂鲁胺能诱导成骨细胞分泌ECM1，其能激活PCa细胞Wnt/β-catenin信号，并通过提高PCa细胞干性促进治疗抵抗,可能是骨微环境来源促进PCa细胞抵抗ARPIs治疗的关键功能因子。然而，ECM1调控PCa细胞抵抗ARPIs治疗的具体分子机制尚不清楚，是亟待回答的科学问题。本项目通过免疫共沉淀、质谱分析、体内外实验及临床研究，阐明ARPIs促进成骨细胞分泌ECM1的机制及ECM1通过激活Wnt/β-catenin信号调控PCa细胞抵抗ARPIs治疗的具体分子机制。为优化骨转移PCa的治疗方案提供新的理论依据。

Hormonal therapy is the first-line therapeutic strategy against bone metastastic prostate cancer (PCa). However, most patients develop resistance to hormonal therapy and eventually progress to the stage of bone metastatic castrate-resistant prostate cancer, which has been the main cause of death. To date, the mechanism of therapy resistance needs to be further clarified. Our previous studies have confirmed that the osteoblast niche is one key prognostic factor of PCa patients with bone metastasis, and may play an important role in inducing therapy resistance for PCa patients. Our previous results found that androgen receptor pathway inhibitors (ARPIs), enzalutamide, can induce osteoblasts to secret ECM1, which can activate Wnt/β-catenin signaling in PCa cells and promote therapy resistance of PCa cells through enhancing their stemness, which may be involved in the therapy resistance of PCa cells to ARPIs in bone microenvironment. However, the specific molecular mechanism of ECM1 regulating PCa cells therapy resistance to ARPIs is unclear, which is a scientific clinical question to be answered urgently. In the future work, in vivo and in vitro experiments will be performed to clarify the molecular mechanism that how ARPIs promote the secretion of ECM1 by osteoblasts, and how ECM1 regulates PCa cells resistance to ARPIs through activating Wnt/β-catenin signaling. The results will provide theoretical basis for developing a novel therapeutic strategy against bone metastatic PCa.