ORIGINAL RESEARCH article
Front. Genet.
Sec. Cancer Genetics and Oncogenomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1615259
Characterization of the phenotype and function of PRELP+ fibroblast subtype in liver metastatic colorectal cancer
Provisionally accepted
- 1Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- 2University of Science and Technology of China, Department of Pharmacy, The First Affiliated Hospital of University of Science and Technology of China Anhui Provincial Hospital, Hefei, Anhui Province, China
- 3First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
- 4Department of Computer Science, University of Liverpool, Liverpool, United Kingdom
- 5HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou, China
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Fibroblasts are critical mediators of tumor progression and metastasis, yet their heterogeneity and function in colorectal cancer (CRC) liver metastases remain incompletely understood. Through scRNA-seq analysis, we identified a distinct PRELP+ fibroblast subtype associated with liver metastasis and tumor progression. We found that PRELP+ CAFs were predominantly enriched in liver metastatic tumors (mLC), less abundant in primary CRC with liver metastasis (mCC), and rare in non-metastatic CRC (nCC). Immunofluorescence assays were performed on histological slides from both mCC and mLC samples, validating the scRNA-seq analysis results. Transcriptomic profiling revealed that PRELP+ CAFs exhibit a unique molecular signature characterized by extracellular matrix components (PRELP, COLEC11, ITGBL1) and activation of tumor-promoting pathways, including TGF-β and Wnt signaling. Pseudotime trajectory analysis indicated that PRELP+ CAFs represent a terminal fibroblast differentiation state. Multiplex immunofluorescence staining revealed spatial colocalization with T cells, B cells, and plasma cells, and cell-cell communication analysis suggested that PRELP+ CAFs contribute to an immunosuppressive tumor microenvironment via APP-CD74 and collagen-CD44 signaling, facilitating immune evasion and tumor progression. Furthermore, NR2F2, JUN and JUND were identified as key transcriptional regulators of both the molecular identity and functional specialization of PRELP+ CAFs. These findings provide new insights into fibroblast heterogeneity in CRC liver metastases and highlight PRELP+ CAFs as potential therapeutic targets.
Keywords: colorectal cancer, liver metastasis, single-cell RNA-seq, Cancer-associatedfibroblasts, PRELP+ CAF, Immunosuppressive TME
Received: 21 Apr 2025; Accepted: 29 Aug 2025.
Copyright: © 2025 Dai, Huang, Sun, Zhang, Yu, Hu, Wu and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Qingfa Wu, University of Science and Technology of China, Department of Pharmacy, The First Affiliated Hospital of University of Science and Technology of China Anhui Provincial Hospital, Hefei, 230001, Anhui Province, China
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