1. PDGFRα+ITGA11+ fibroblasts foster early-stage cancer lymphovascular invasion and lymphatic metastasis via ITGA11-SELE interplay.
- Author
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Zheng, Hanhao, An, Mingjie, Luo, Yuming, Diao, Xiayao, Zhong, Wenlong, Pang, Mingrui, Lin, Yan, Chen, Jiancheng, Li, Yuanlong, Kong, Yao, Zhao, Yue, Yin, Yina, Ai, Le, Huang, Jian, Chen, Changhao, and Lin, Tianxin
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LYMPHATIC metastasis , *FIBROBLASTS , *RNA sequencing , *BLADDER cancer , *ENDOTHELIAL cells - Abstract
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. [Display omitted] • A CAF subset that expresses PDGFRα and ITGA11 is identified in early-stage BCa • PDGFRα+ITGA11+ CAFs enhance lymphangiogenesis via ITGA11-SELE interplay • PDGFRα+ITGA11+ CAFs align ECM via CHI3L1 to assist BCa cell intravasation • Targeting PDGFRα+ITGA11+ CAFs inhibits LVI and LN metastasis of early-stage BCa Zheng et al. uncover the cellular landscape in early-stage BCa and report a CAF subset characterized by PDGFRα and ITGA11. They demonstrate that PDGFRα+ITGA11+ CAFs stimulate lymphangiogenesis and align ECM to assist BCa cell intravasation, facilitating the LVI and LN metastasis of early-stage BCa, which provides a potential therapeutic target. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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