ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1687485
A spatially resolved single-cell landscape of colorectal cancer liver metastasis reveals a stromal-tumor glycolytic signaling interaction
Provisionally accepted
- 1Department of Colorectal Surgery, The First Affiliated Hospital of Fujian Medical University, Fujian Medical University, Fuzhou 350005, China
- 2Department of Colorectal Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
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Background: Colorectal cancer (CRC) remains a leading cause of cancer mortality, with liver metastasis being the principal determinant of poor prognosis,but the spatial mechanisms orchestrating metastatic niches remain elusive. Method: To dissect the molecular and spatial dynamics of CRC progression, we constructed an integrative atlas using 35 single-cell RNA-seq datasets and spatial transcriptomics from primary tumors, liver metastases, and matched normal tissues. Malignant epithelial subpopulations were stratified via inferCNV and CytoTRACE analyses. Stromal-tumor interactions were dissected using CellChat and NicheNet, with functional validation through in vitro co-culture and immunohistochemistry. Result: We identified a transcriptionally distinct epithelial subpopulation, termed high-malignancy CRC (High-M CRC), enriched in metastatic lesions and characterized by enhanced stemness, MYC-driven transcriptional activity, and glycolytic reprogramming. Stromal-tumor interaction analyses revealed that cancer-associated fibroblasts (CAFs), particularly matrix CAFs (mCAFs), promote malignant progression via the HGF-MET-MYC signaling axis. Spatial transcriptomic mapping confirmed the physical proximity and molecular co-localization of High-M CRC cells and mCAFs, along with enriched glycolysis and MYC expression at the cell-cell interface. In vitro functional validation demonstrated that CAF-derived HGF activates MET-MYC signaling in CRC cells, enhancing their invasion and proliferation—effects reversible by MET knockdown. Conclusion: We unveil a spatially organized metabolic niche driven by stromal-tumor HGF-MET-MYC signaling.These findings offer novel insights into the stromal-tumor interaction and suggest actionable targets for therapeutic intervention in CRC.
Keywords: Colorectal cancer liver metastasis, Single-cell and spatial transcriptomics, High-malignancy CRC subpopulation, HGF-MET-MYC signaling axis, Spatial stromal-tumor co-localization
Received: 17 Aug 2025; Accepted: 15 Oct 2025.
Copyright: © 2025 Chen, Wang, Zhu and Guan. 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: Guoxian Guan, fjxhggx@163.com
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