中山大学Tianxin Lin和Changhao Chen研究组合作的最新研究表明，PDGFRα⁺ITGA11⁺成纤维细胞通过ITGA11- sele相互作用促进早期癌症淋巴血管侵袭和淋巴转移。这一研究成果于2024年2月29日发表在国际学术期刊《癌细胞》上。

利用单细胞RNA 测序和空间转录组学，研究人员在早期膀胱癌（BCa）患者中发现了之前未知的PDGFRα⁺ITGA11⁺ 癌症相关成纤维细胞(CAFs) 群。对910例病人进行的多中心临床分析证实，PDGFRα⁺ITGA11⁺ CAF与早期膀胱癌患者的淋巴管侵袭（LVI）和不良预后有关。

PPDGFRα⁺ITGA11⁺ CAFs特异性缺失小鼠模型证明，这些CAFs有助于早期BCa的淋巴管入侵和淋巴结（LN）转移。

从机制上讲，PDGFRα⁺ITGA11⁺  CAFs通过识别淋巴内皮细胞中ITGA11的表面受体SELE来激活SRC-p-VEGFR3-MAPK通路，从而促进淋巴管生成。

此外，PDGFRα⁺ITGA11⁺ CAFs中的CHI3L通过介导周围基质排布帮助癌细胞内侵，促进早期Bca淋巴管转移和淋巴结转移。总之，该研究揭示了PDGFRα⁺ITGA11⁺ CAFs在癌症转移过程中的关键作用，为早期BCa LVI的治疗提供了参考。

据介绍，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和机制仍不清楚。

附：英文原文

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

Author: Hanhao Zheng, Mingjie An, Yuming Luo, Xiayao Diao, Wenlong Zhong, Mingrui Pang, Yan Lin, Jiancheng Chen, Yuanlong Li, Yao Kong, Yue Zhao, Yina Yin, Le Ai, Jian Huang, Changhao Chen, Tianxin Lin

Issue&Volume: 2024-02-29

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.

DOI: 10.1016/j.ccell.2024.02.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00046-1