P4HA1⁺ collagen-modifying fibroblasts are associated with pro-tumor niches and therapeutic vulnerabilities in colorectal cancer.
7 affiliations
- 1The Center for Clinical Molecular Medical Detection, Engineering Research Center of Chongqing Education Commission of China for IVD Technology Innovation and Translation, Laboratory Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- 2School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics, Chongqing Medical University, Ministry of Education, Chongqing, China.
- 3Laboratory of Neurological Diseases and Interdisciplinary Medicine, Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- 4Department of Clinical Laboratory, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, China. [email protected].
- 5School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics, Chongqing Medical University, Ministry of Education, Chongqing, China. [email protected].
- 6Department of Clinical Laboratory, Dazhou Dachuan District People's Hospital, Dazhou, Sichuan, China. [email protected].
- 7The Center for Clinical Molecular Medical Detection, Engineering Research Center of Chongqing Education Commission of China for IVD Technology Innovation and Translation, Laboratory Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
Abstract
Background
Cancer-associated fibroblasts (CAFs) are a major stromal component of the tumor microenvironment (TME) and actively participate in tumor progression. Although CAF heterogeneity in colorectal cancer (CRC) is increasingly recognized, how individual CAF subpopulations simultaneously coordinate extracellular matrix (ECM) remodeling, angiogenesis, and immune suppression within spatially organized niches remains poorly understood.Methods
CAF heterogeneity was systematically analyzed by integrating single-cell RNA sequencing, spatial transcriptomics, and bulk transcriptomic data. By combining cell clustering, pseudotime analysis, transcriptional regulatory network inference, spatial deconvolution, and ligand-receptor interaction analysis, we revealed the spatial distribution and cellular communication characteristics of CAF subpopulations. At the same time, machine learning-based prognostic models and transcriptional perturbation analysis were used to evaluate the clinical significance and potential therapeutic value of CAF-related transcriptional programs.Results
We identified a prolyl 4-hydroxylase subunit alpha 1 (P4HA1)-positive collagen-modifying CAF subpopulation (P4HA1⁺ CAFs) that was enriched in tumor tissue and exhibited collagen remodeling characteristics. This subpopulation preferentially localized at the tumor-stroma interface, co-localizing with pro-angiogenic endothelial cells, immunosuppressive macrophages, and malignant epithelial cells to form a spatially organized niche with concurrent ECM remodeling, angiogenesis, and immune suppression. P4HA1⁺ CAFs were predicted to engage distinct ligand-receptor axes, including WNT5A-MCAM with endothelial cells, MDK-LRP1 with macrophages, and MDK-NCL with malignant epithelial cells. The MDK-NCL axis was associated with increased RANBP1 expression and enhanced tumor cell proliferation and invasion. Machine learning analysis further identified P4HA1, TIMP1, ARL4C, and SFRP4 as stable core genes associated with poor prognosis. Drug perturbation analysis showed that 2-methoxyestradiol and its combination with the histone deacetylase (HDAC) inhibitor JNJ-26,481,585 may partially reverse the malignant transcriptional program of P4HA1⁺ CAFs.Conclusions
This study characterizes a P4HA1⁺ collagen-modifying CAF subpopulation that resides within a spatially organized multicellular niche and engages distinct signaling axes to simultaneously promote angiogenesis, immune suppression, and tumor cell proliferation in CRC, highlighting its prognostic and potential therapeutic value.
Related
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- Cancer-Associated Fibroblasts in Perineural Invasion: Biological Roles and Therapeutic Strategies
BibTeX
@article{gui2026p4ha1,
title = {{P4HA1⁺ collagen-modifying fibroblasts are associated with pro-tumor niches and therapeutic vulnerabilities in colorectal cancer.}},
author = {Kai Gui and Yan Chen and Qinqin Du and Ke Lv and Weitao Wang and Ziyun Li and Yuhang Cheng and Wenyan Wu and Min Tang and Cheng Zhang and Li Wang},
journal = {Journal of translational medicine},
year = {2026},
month = jul,
doi = {10.1186/s12967-026-08678-x},
url = {https://europepmc.org/article/MED/42902379},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - P4HA1⁺ collagen-modifying fibroblasts are associated with pro-tumor niches and therapeutic vulnerabilities in colorectal cancer.
AU - Kai Gui
AU - Yan Chen
AU - Qinqin Du
AU - Ke Lv
AU - Weitao Wang
AU - Ziyun Li
AU - Yuhang Cheng
AU - Wenyan Wu
AU - Min Tang
AU - Cheng Zhang
AU - Li Wang
PY - 2026
DA - 2026/07/01
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08678-x
UR - https://europepmc.org/article/MED/42902379
AB - Background Cancer-associated fibroblasts (CAFs) are a major stromal component of the tumor microenvironment (TME) and actively participate in tumor progression. Although CAF heterogeneity in colorectal cancer (CRC) is increasingly recognized, how individual CAF subpopulations simultaneously coordinate extracellular matrix (ECM) remodeling, angiogenesis, and immune suppression within spatially organized niches remains poorly understood.Methods CAF heterogeneity was systematically analyzed by integrating single-cell RNA sequencing, spatial transcriptomics, and bulk transcriptomic data. By combining cell clustering, pseudotime analysis, transcriptional regulatory network inference, spatial deconvolution, and ligand-receptor interaction analysis, we revealed the spatial distribution and cellular communication characteristics of CAF subpopulations. At the same time, machine learning-based prognostic models and transcriptional perturbation analysis were used to evaluate the clinical significance and potential therapeutic value of CAF-related transcriptional programs.Results We identified a prolyl 4-hydroxylase subunit alpha 1 (P4HA1)-positive collagen-modifying CAF subpopulation (P4HA1⁺ CAFs) that was enriched in tumor tissue and exhibited collagen remodeling characteristics. This subpopulation preferentially localized at the tumor-stroma interface, co-localizing with pro-angiogenic endothelial cells, immunosuppressive macrophages, and malignant epithelial cells to form a spatially organized niche with concurrent ECM remodeling, angiogenesis, and immune suppression. P4HA1⁺ CAFs were predicted to engage distinct ligand-receptor axes, including WNT5A-MCAM with endothelial cells, MDK-LRP1 with macrophages, and MDK-NCL with malignant epithelial cells. The MDK-NCL axis was associated with increased RANBP1 expression and enhanced tumor cell proliferation and invasion. Machine learning analysis further identified P4HA1, TIMP1, ARL4C, and SFRP4 as stable core genes associated with poor prognosis. Drug perturbation analysis showed that 2-methoxyestradiol and its combination with the histone deacetylase (HDAC) inhibitor JNJ-26,481,585 may partially reverse the malignant transcriptional program of P4HA1⁺ CAFs.Conclusions This study characterizes a P4HA1⁺ collagen-modifying CAF subpopulation that resides within a spatially organized multicellular niche and engages distinct signaling axes to simultaneously promote angiogenesis, immune suppression, and tumor cell proliferation in CRC, highlighting its prognostic and potential therapeutic value.
SN - 1479-5876
ER -