1. Academic Validation
  2. PDGFRα+ITGA11+ fibroblasts foster early-stage cancer lymphovascular invasion and lymphatic metastasis via ITGA11-SELE interplay

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

  • Cancer Cell. 2024 Feb 23:S1535-6108(24)00046-1. doi: 10.1016/j.ccell.2024.02.002.
Hanhao Zheng 1 Mingjie An 1 Yuming Luo 2 Xiayao Diao 3 Wenlong Zhong 1 Mingrui Pang 1 Yan Lin 1 Jiancheng Chen 1 Yuanlong Li 1 Yao Kong 2 Yue Zhao 4 Yina Yin 5 Le Ai 5 Jian Huang 1 Changhao Chen 6 Tianxin Lin 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China.
  • 3 Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 Department of Tumor Intervention, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, P.R. China.
  • 5 Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P.R. China.
  • 6 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. Electronic address: chenchh53@mail.sysu.edu.cn.
  • 7 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. Electronic address: lintx@mail.sysu.edu.cn.
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.

Keywords

PDGFRα(+)ITGA11(+) CAFs; SELE; early-stage bladder cancer; extracellular matrix; lymphovascular invasion.

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