Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
School of Basic Medical Sciences, Fudan University, Shanghai, China.
Cancer Lett. 2023 Jul 10;566:216244. doi: 10.1016/j.canlet.2023.216244. Epub 2023 May 26.
Castration-resistant prostate cancer (CRPC) responds poorly to existing therapy and appears as the lethal consequence of prostate cancer (PCa) progression. The tumour microenvironment (TME) has been thought to play a crucial role in CRPC progression. Here, we conducted single-cell RNA sequencing analysis on two CRPC and two hormone-sensitive prostate cancer (HSPC) samples to reveal potential leading roles in castration resistance. We described the single-cell transcriptional landscape of PCa. Higher cancer heterogeneity was explored in CRPC, with stronger cell cycling status and heavier copy number variant burden of luminal cells. Cancer-associated fibroblasts (CAFs), which are one of the most critical components of TME, demonstrated unique expression and cell-cell communication features in CRPC. A CAFs subtype with high expression of HSD17B2 in CRPC was identified with inflammatory features. HSD17B2 catalyses the conversion of testosterone and dihydrotestosterone to their less active forms, which was associated with steroid hormone metabolism in PCa tumour cells. However, the characteristics of HSD17B2 in PCa fibroblasts remained unknown. We found that HSD17B2 knockdown in CRPC-CAFs could inhibit migration, invasion, and castration resistance of PCa cells in vitro. Further study showed that HSD17B2 could regulate CAFs functions and promote PCa migration through the AR/ITGBL1 axis. Overall, our study revealed the important role of CAFs in the formation of CRPC. HSD17B2 in CAFs regulated AR activation and subsequent ITGBL1 secretion to promote the malignant behaviour of PCa cells. HSD17B2 in CAFs could serve as a promising therapeutic target for CRPC.
去势抵抗性前列腺癌（CRPC）对现有治疗反应不佳，似乎是前列腺癌（PCa）进展的致命后果。肿瘤微环境（TME）被认为在 CRPC 进展中起关键作用。在这里，我们对两个 CRPC 和两个激素敏感性前列腺癌（HSPC）样本进行了单细胞 RNA 测序分析，以揭示潜在的抗阉割作用。我们描述了 PCa 的单细胞转录景观。在 CRPC 中探索了更高的癌症异质性，具有更强的细胞循环状态和更多的 luminal 细胞拷贝数变异负担。癌症相关成纤维细胞（CAFs）是 TME 中最关键的成分之一，在 CRPC 中表现出独特的表达和细胞间通讯特征。在 CRPC 中鉴定出一种具有高表达 HSD17B2 的 CAFs 亚型，具有炎症特征。HSD17B2 催化睾酮和二氢睾酮转化为其活性较低的形式，这与 PCa 肿瘤细胞中的类固醇激素代谢有关。然而，PCa 成纤维细胞中 HSD17B2 的特征尚不清楚。我们发现，CRPC-CAFs 中的 HSD17B2 敲低可以抑制 PCa 细胞的迁移、侵袭和抗阉割作用。进一步的研究表明，HSD17B2 可以通过 AR/ITGBL1 轴调节 CAFs 的功能并促进 PCa 迁移。总体而言，我们的研究揭示了 CAFs 在 CRPC 形成中的重要作用。CAFs 中的 HSD17B2 通过 AR/ITGBL1 轴调节 AR 激活和随后的 ITGBL1 分泌，从而促进 PCa 细胞的恶性行为。CAFs 中的 HSD17B2 可以作为 CRPC 的一个有前途的治疗靶点。
