产生THBS2的基质癌相关成纤维细胞通过CD47-MAPK轴促进结直肠癌进展并与不良预后相关。

THBS2-producing matrix CAFs promote colorectal cancer progression and link to poor prognosis via the CD47-MAPK axis.

作者信息

Liu Zaoqu, Ba Yuhao, Shan Dan, Zhou Xing, Zuo Anning, Zhang Yuyuan, Xu Hui, Liu Shutong, Liu Benyu, Zhao Yanan, Weng Siyuan, Wang Ruizhi, Deng Jinhai, Luo Peng, Cheng Quan, Hu Xin, Yang Shuaixi, Wang Fubing, Han Xinwei

机构信息

Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.

Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

出版信息

Cell Rep. 2025 Apr 22;44(4):115555. doi: 10.1016/j.celrep.2025.115555. Epub 2025 Apr 12.

DOI:10.1016/j.celrep.2025.115555

PMID:40222008

Abstract

Cancer-associated fibroblasts (CAFs) display significant functional and molecular heterogeneity within the tumor microenvironment, playing diverse roles in cancer progression. Employing single-cell RNA sequencing data of colorectal cancer (CRC), we identified a subset of matrix CAFs (mCAFs) as a critical subtype that secretes THBS2, a molecule linked to advanced cancer stages and poor prognosis. Spatial transcriptomics and multiplex immunohistochemistry revealed clear spatial colocalization between THBS2-producing mCAFs and tumor cells. Mechanically, CAF-secreted THBS2 binds to CD47 on tumor cells, triggering the MAPK/ERK5 signaling pathway, which enhances tumor progression. The tumor-promoting role of THBS2 was further validated using fibroblast-specific THBS2 knockout mice, patient-derived organoids, and xenografts. Moreover, the transcription factor CREB3L1 was identified as a regulator of the transformation of normal fibroblasts into THBS2-producing mCAFs. These findings underscore the pivotal role of THBS2 in CRC progression and highlight the therapeutic potential of targeting the THBS2-CD47 axis and CREB3L1 in CRC.

摘要

癌症相关成纤维细胞（CAFs）在肿瘤微环境中表现出显著的功能和分子异质性，在癌症进展中发挥着多种作用。利用结直肠癌（CRC）的单细胞RNA测序数据，我们鉴定出基质CAFs（mCAFs）的一个亚群是一种关键亚型，该亚型分泌THBS2，这是一种与癌症晚期和不良预后相关的分子。空间转录组学和多重免疫组化显示，产生THBS2的mCAFs与肿瘤细胞之间存在明显的空间共定位。在机制上，CAF分泌的THBS2与肿瘤细胞上的CD47结合，触发MAPK/ERK5信号通路，从而促进肿瘤进展。使用成纤维细胞特异性THBS2基因敲除小鼠、患者来源的类器官和异种移植进一步验证了THBS2的促肿瘤作用。此外，转录因子CREB3L1被确定为正常成纤维细胞向产生THBS2的mCAFs转化的调节因子。这些发现强调了THBS2在CRC进展中的关键作用，并突出了靶向THBS2-CD47轴和CREB3L1在CRC治疗中的潜力。