Single-cell transcriptomic and immune microenvironment analyses reveal a TIMP1-associated OLFM4⁺ tumor epithelial program linked to colorectal cancer progression and immune evasion.
8 affiliations
- 1Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China. Electronic address: [email protected].
- 2Department of Reproductive Medicine, Hubei University of Medicine, Xiangyang No. 1 People's Hospital, Xiangyang, China.
- 3Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
- 4Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, People's Republic of China.
- 5Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250014, China. Electronic address: [email protected].
- 6Department of Traditional Chinese Medicine (TCM) Proctology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, China. Electronic address: [email protected].
- 7Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. Electronic address: [email protected].
- 8Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China. Electronic address: [email protected].
Abstract
Background
Colorectal cancer (CRC) is characterized by marked epithelial heterogeneity and dynamic tumor-microenvironment interactions. However, epithelial states associated with progression across the normal-adenoma-carcinoma sequence remain incompletely defined.Methods
Single-cell RNA sequencing data from normal colorectal mucosa, adenoma, and tumor tissues were analyzed using inferCNV, Monocle, Slingshot, CytoTRACE, CellChat, and SCENIC. An OLFM4⁺ tumor cell risk score (OTRS) was constructed using Cox and LASSO regression, and TIMP1 function was evaluated in vitro.Results
Eight major cell types and nine tumor epithelial subtypes were identified. C3 OLFM4⁺ cells showed elevated transcriptional activity, stemness, metabolic activity, and greater representation in carcinoma than adenoma tissues. Trajectory analyses positioned these cells in an early-to-intermediate transitional state. CellChat predicted prominent fibroblast-C3 OLFM4⁺ interactions, including a putative WNT2B-FZD/LRP axis, while SCENIC identified XBP1, NFIA, PPARG, HDAC2, and UBE2K as subtype-associated regulators. The C3 OLFM4⁺-derived OTRS stratified prognosis; high OTRS was associated with poorer survival, macrophage-enriched infiltration, higher stromal, immune, and TIDE scores, and differential predicted drug sensitivity. TIMP1 knockdown suppressed malignant behaviors in CRC cells.Conclusion
C3 OLFM4⁺ cells represent a stem-like, metabolically active tumor epithelial state associated with CRC progression, fibroblast-derived WNT signaling, immune-evasion-related features, and unfavorable prognosis. The OTRS model may support prognostic and therapeutic assessment, while TIMP1 contributes to malignant CRC cell behavior.
Related
- TENASCIN-Dependent Mesenchymal–Epithelial Interactions Associated with Interstitial Microenvironment Remodeling in Cattle-Yak Lung: Insights from Single-Nucleus Transcriptomics
- Single-cell and bulk transcriptomic analysis of inflammation-metabolism programs and the tumor microenvironment of colorectal cancer liver metastasis
- VIRMA-associated SRD5A2 downregulation promotes BPH progression through ERα-CREB5-dependent epithelial plasticity
- SLC35D1 Is Associated with Colorectal Cancer Progression, EMT-Related Phenotypes, and Immune Infiltration
- Intratumoural Bacterial Co-Occurrence is Associated With an Altered Tumour Immune Microenvironment and Poor Prognosis in Colorectal Cancer.
BibTeX
@article{leng2026singlecell,
title = {{Single-cell transcriptomic and immune microenvironment analyses reveal a TIMP1-associated OLFM4⁺ tumor epithelial program linked to colorectal cancer progression and immune evasion.}},
author = {Rui Leng and Xi Cui and Xinyu Wu and Yang Zhao and Lei Sun and Haimin Jin and Wenzhi Li and Jiang Lin},
journal = {Translational oncology},
year = {2026},
month = oct,
doi = {10.1016/j.tranon.2026.103066},
url = {https://europepmc.org/article/MED/42887063},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Single-cell transcriptomic and immune microenvironment analyses reveal a TIMP1-associated OLFM4⁺ tumor epithelial program linked to colorectal cancer progression and immune evasion.
AU - Rui Leng
AU - Xi Cui
AU - Xinyu Wu
AU - Yang Zhao
AU - Lei Sun
AU - Haimin Jin
AU - Wenzhi Li
AU - Jiang Lin
PY - 2026
DA - 2026/10/16
JO - Translational oncology
DO - 10.1016/j.tranon.2026.103066
UR - https://europepmc.org/article/MED/42887063
AB - Background Colorectal cancer (CRC) is characterized by marked epithelial heterogeneity and dynamic tumor-microenvironment interactions. However, epithelial states associated with progression across the normal-adenoma-carcinoma sequence remain incompletely defined.Methods Single-cell RNA sequencing data from normal colorectal mucosa, adenoma, and tumor tissues were analyzed using inferCNV, Monocle, Slingshot, CytoTRACE, CellChat, and SCENIC. An OLFM4⁺ tumor cell risk score (OTRS) was constructed using Cox and LASSO regression, and TIMP1 function was evaluated in vitro.Results Eight major cell types and nine tumor epithelial subtypes were identified. C3 OLFM4⁺ cells showed elevated transcriptional activity, stemness, metabolic activity, and greater representation in carcinoma than adenoma tissues. Trajectory analyses positioned these cells in an early-to-intermediate transitional state. CellChat predicted prominent fibroblast-C3 OLFM4⁺ interactions, including a putative WNT2B-FZD/LRP axis, while SCENIC identified XBP1, NFIA, PPARG, HDAC2, and UBE2K as subtype-associated regulators. The C3 OLFM4⁺-derived OTRS stratified prognosis; high OTRS was associated with poorer survival, macrophage-enriched infiltration, higher stromal, immune, and TIDE scores, and differential predicted drug sensitivity. TIMP1 knockdown suppressed malignant behaviors in CRC cells.Conclusion C3 OLFM4⁺ cells represent a stem-like, metabolically active tumor epithelial state associated with CRC progression, fibroblast-derived WNT signaling, immune-evasion-related features, and unfavorable prognosis. The OTRS model may support prognostic and therapeutic assessment, while TIMP1 contributes to malignant CRC cell behavior.
SN - 1936-5233
ER -