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 PDGFRα⁺ITGA11⁺ CAF subset in early-stage bladder cancer (BCa). Multicenter clinical analysis of a 910-case cohort confirms that PDGFRα⁺ITGA11⁺ 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 PDGFRα⁺ITGA11⁺ CAFs-specific deficient mouse model. Mechanistically, PDGFRα⁺ITGA11⁺ CAFs promote lymphangiogenesis via recognizing ITGA11 surface receptor SELE on lymphatic endothelial cells to activate SRC-p-VEGFR3-MAPK pathway. Further, CHI3L1 from PDGFRα⁺ITGA11⁺ 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 PDGFRα⁺ITGA11⁺ CAFs in shaping metastatic landscape, informing the treatment of early-stage BCa LVI.

癌症相关成纤维细胞（CAF）在晚期癌症中表现出相当大的异质性；然而，CAF 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) 中鉴定出了先前未知的 PDGFRα ⁺ ITGA11 ⁺ CAF 子集。 910 例队列的多中心临床分析证实，PDGFRα ⁺ ITGA11 ⁺ CAF 与早期 BCa 的淋巴血管侵犯 (LVI) 和不良预后相关。这些 CAF 促进早期 BCa 中的 LVI 和淋巴结 (LN) 转移，如 PDGFRα ⁺ ITGA11 ⁺ CAF 特异性缺陷小鼠模型所证明。从机制上来说，PDGFRα ⁺ ITGA11 ⁺ CAFs通过识别淋巴管内皮细胞上的ITGA11表面受体SELE来激活SRC-p-VEGFR3-MAPK通路，从而促进淋巴管生成。此外，来自 PDGFRα ⁺ ITGA11 ⁺ CAF 的 CHI3L1 会对齐周围基质，以协助癌细胞内渗，促进早期 BCa LVI 和 LN 转移。总的来说，我们的研究揭示了 PDGFRα ⁺ ITGA11 ⁺ CAF 在塑造转移景观中的关键作用，为早期 BCa LVI 的治疗提供了信息。