Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China.
Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China.
Cancer Cell. 2024 Apr 8;42(4):682-700.e12. doi: 10.1016/j.ccell.2024.02.002. Epub 2024 Feb 29.
Cancer-associated fibroblasts (CAFs) exhibit considerable heterogeneity in advanced cancers; however, the functional annotation and mechanism of CAFs in early-stage cancers remain elusive. Utilizing single-cell RNA sequencing and spatial transcriptomic, we identify a previously unknown PDGFRαITGA11 CAF subset in early-stage bladder cancer (BCa). Multicenter clinical analysis of a 910-case cohort confirms that PDGFRαITGA11 CAFs are associated with lymphovascular invasion (LVI) and poor prognosis in early-stage BCa. These CAFs facilitate LVI and lymph node (LN) metastasis in early-stage BCa, as evidenced in a PDGFRαITGA11 CAFs-specific deficient mouse model. Mechanistically, PDGFRαITGA11 CAFs promote lymphangiogenesis via recognizing ITGA11 surface receptor SELE on lymphatic endothelial cells to activate SRC-p-VEGFR3-MAPK pathway. Further, CHI3L1 from PDGFRαITGA11 CAFs aligns the surrounding matrix to assist cancer cell intravasation, fostering early-stage BCa LVI and LN metastasis. Collectively, our study reveals the crucial role of PDGFRαITGA11 CAFs in shaping metastatic landscape, informing the treatment of early-stage BCa LVI.
癌症相关成纤维细胞（CAFs）在晚期癌症中表现出相当大的异质性；然而，CAFs 在早期癌症中的功能注释和机制仍然难以捉摸。利用单细胞 RNA 测序和空间转录组学，我们在早期膀胱癌（BCa）中鉴定出一个以前未知的 PDGFRαITGA11 CAF 亚群。对包含 910 例病例的多中心临床分析证实，PDGFRαITGA11 CAFs 与早期 BCa 的血管淋巴管侵犯（LVI）和不良预后相关。在 PDGFRαITGA11 CAFs 特异性缺失小鼠模型中证实了这些 CAFs 促进了早期 BCa 的 LVI 和淋巴结（LN）转移。在机制上，PDGFRαITGA11 CAFs 通过识别淋巴管内皮细胞上的 ITGA11 表面受体 SELE 来促进淋巴管生成，从而激活 SRC-p-VEGFR3-MAPK 途径。此外，来自 PDGFRαITGA11 CAFs 的 CHI3L1 排列周围基质以协助癌细胞浸润，促进早期 BCa 的 LVI 和 LN 转移。总的来说，我们的研究揭示了 PDGFRαITGA11 CAFs 在塑造转移景观中的关键作用，为早期 BCa 的 LVI 治疗提供了信息。
