PDGFRα+ITGA11+ fibroblasts foster early-stage cancer lymphovascular invasion and lymphatic metastasis via ITGA11-SELE interplay

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.