雄激素剥夺驱动CD90/ITGBL1双阳性CAFs亚群富集促进前列腺癌化疗抵抗的机制研究

多西他赛对于去势抵抗性前列腺癌（CRPC）的化疗效果明显弱于激素敏感性前列腺癌（HSPC），具体机制不明。肿瘤相关成纤维细胞（CAFs）是肿瘤微环境中含量最丰富的基质细胞，具有显著的异质性。我们前期研究发现，与HSPC患者的CAFs相比，CRPC患者的CAFs能够显著促进多西他赛化疗抵抗。进一步研究显示，CRPC患者CD90/ITGBL1双阳性的CAFs亚群（CAF90IT++）在雄激素剥夺治疗（ADT）后显著富集。据此我们提出假设：ADT治疗导致前列腺癌CAFs异质性逐渐失衡，CAF90IT++亚群富集并促进多西他赛化疗抵抗。我们拟在临床样本和体内外实验中进一步探索CAF90IT++亚群被ADT治疗富集后通过分泌ITGBL1作用于肿瘤细胞促进多西他赛化疗抵抗的具体作用和分子机制，为临床实践中尽早开始多西他赛化疗提供坚实的理论基础，并为已经进入CRPC阶段的患者寻找化疗增敏的潜在靶点。

Docetaxel has been recommended as a first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) by NCCN guidelines, but the survival benefit of docetaxel is much less prominent when given at the castration-resistant period, compared with at the time of androgen deprivation therapy (ADT) initiation. Recently, it has been found that intervention of tumor microenvironment (TME) seems to be a new approach to regulate advanced prostate cancer. Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in TME, which appear to be significant heterogeneous. Our newly studies found that, compared with the CAFs from hormone-sensitive prostate cancer (HSPC) patients (CAFhs), the CAFs from CRPC patients (CAFcr) significantly promoted resistance to docetaxel chemotherapy in prostate cancer. Further investigation revealed that a new CAFs subset with high expression of cell surface marker CD90 and secreted protein ITGBL1 (CAF90IT++), was observably enriched in TME after ADT, which played a major role in promoting chemo-resistance of prostate cancer cells by secreting ITGBL1. Therefore, we hypothesize that stromal fibroblasts are initially heterogeneous in TME of HSPC, but along with ADT, the balance of CAFs heterogeneity is gradually broken and CAF90IT++ subset is enriched to promote chemo-resistance of prostate cancer. In this study, in vitro cell assays, in vivo mouse models, and clinical tissue samples will be applied to investigate the molecular mechanism underlying docetaxel resistance, and the expected results will help to provide a sound theoretical basis that docetaxel should be employed as early as at the initiation of long-term hormone therapy, as well as potential targets for developing new strategies for those who has been castration-resistant.