Identification of a unique subpopulation of mucosal fibroblasts in colorectal cancer with tumor-restraining characteristics

초록

While tumor-restraining cancer-associated fibroblasts (Tr-CAFs) have been investigated in various cancers, their existence in colorectal cancer remains unexplored. We performed a comprehensive analysis of diverse colorectal cancer datasets, including single-cell RNA-seq/ATAC-seq data from colorectal samples, TCGA RNA-seq, and histological samples. We identified a fibroblast subpopulation uniquely expressing ADAMDEC1, CXCL14, EDNRB, and PROCR, strongly associated with favorable patient outcomes, implicating their role as Tr-CAFs. Pseudotime trajectory analysis suggested these cells as terminally differentiated mucosal fibroblasts. Pathway analysis indicated that this subpopulation was significantly associated with tumor-suppressive functions, such as reduced extracellular matrix secretion, augmented immune response, and enhanced responsiveness to immunotherapy. Single-cell ATAC-seq analysis revealed that this putative Tr-CAF subset exhibited unique epigenetic profiles characterized by superenhancer-regulated tumor-suppressive genes, thereby supporting its identity as a stable lineage rather than a transient phenotypic state induced by external stimuli. Immunohistochemistry showed that key markers identifying this putative Tr-CAF subset-CXCL14, ADAMDEC1, EDNRB, and PROCR-were predominantly localized to fibroblasts within normal colonic mucosa and less frequently in cancer-associated fibroblasts (CAFs). Their expression levels exhibited statistically significant associations with favorable clinicopathological indicators, including prolonged disease-free survival. Notably, ADAMDEC1 expression in CAFs was significantly correlated with T-cell infiltration within the tumor microenvironment. In conclusion, our investigation elucidates the characteristics and clinical relevance of Tr-CAFs in colorectal cancer, suggesting novel avenues for targeted anti-CAF therapy. (c) 2025 The Author(s). Published by Elsevier Inc. on behalf of Korean Society for Molecular and Cellular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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