Liu, Z. and Ba, Y. and Shan, D. and Zhou, X. and Zuo, A. and Zhang, Y. and Xu, H. and Liu, S. and Liu, B. and Zhao, Y. and Weng, S. and Wang, R. and Deng, J. and Luo, P. and Cheng, Q. and Hu, X. and Yang, S. and Wang, F. and Han, X. (2025) THBS2-producing matrix CAFs promote colorectal cancer progression and link to poor prognosis via the CD47-MAPK axis. Cell Reports, 44 (4): 115555. ISSN 2211-1247
Full text not available from this repository.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.