A renal cyst-clear cell renal cell carcinoma comorbidity analysis identifies a FOXM1-positive epithelial COL6A1-CD44 axis that remodels fibroblasts.
9 affiliations
- 1Department of Urology, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, Henan, China.
- 2Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China.
- 3Department of Urology, The First Naval Hospital of Southern Theater Command, Zhanjiang, China.
- 4Department of Urology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
- 5Department of Urology, Henan Corps Hospital of Chinese People's Armed Police Force, Zhengzhou, Henan, China. Electronic address: [email protected].
- 6Department of Urology, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, Henan, China. Electronic address: [email protected].
- 7Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China. Electronic address: [email protected].
- 8Department of Urology, The Frist Hospital of Jiaxing, Frist Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China. Electronic address: [email protected].
- 9Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China. Electronic address: [email protected].
Abstract
Background
Renal cystic conditions are heterogeneous. We used a broad renal cyst-associated disease-gene framework to identify molecular programs shared with clear cell renal cell carcinoma (ccRCC), without modeling a specific cystic disorder or direct cyst-to-cancer progression.Methods
We identified 237 shared genes between renal cyst disease and ccRCC (TCGA-KIRC), performed functional enrichment, Mendelian randomization, and built a random survival forest (RSF) risk score benchmarked against published signatures and immunotherapy cohorts. Single-cell (Scissor, SCENIC, scTenifoldKnk virtual FOXM1 knockout) and spatial transcriptomics (RCTD, CellChat) were integrated with fibroblast subclustering and oncoPredict drug screening. Candidate FOXM1 inhibitors were prioritized by docking and 100-ns molecular dynamics, with isovitexin validated functionally.Results
The shared program was enriched for epithelial development and ECM remodeling. Two direction-specific Mendelian randomization analyses supported associations between genetic liability to kidney cancer and related renal cystic phenotypes. The RSF score showed robust prognostic discrimination across cohorts and separated immunotherapy outcomes. High-risk tumors were enriched for Tregs, B cells, and fibroblasts. FOXM1+ malignant epithelium represented the high-risk state, with elevated CNV burden and regulon activity; virtual FOXM1 knockout identified COL6A1 and CD44 among 129 significant non-target perturbation hits. Convergent single-cell and spatial analyses nominated a COL6A1-CD44 communication axis associated with fibroblast remodeling, with F5_SFRP2⁺ fibroblasts as the most plausible receiving state. These fibroblasts showed ECM-remodeling, adverse prognosis, and pathway activation. Isovitexin emerged as a lead FOXM1-targeting compound, significantly suppressing ccRCC proliferation, migration, and invasion.Conclusions
These findings support a testable communication model involving FOXM1+ epithelium, COL6A1-CD44 and F5_SFRP2+ fibroblasts. The in vitro results also support further evaluation of isovitexin in ccRCC.
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BibTeX
@article{lv2026renal,
title = {{A renal cyst-clear cell renal cell carcinoma comorbidity analysis identifies a FOXM1-positive epithelial COL6A1-CD44 axis that remodels fibroblasts.}},
author = {Hao Lv and Chenyi Ge and Yuming Jin and Yu Fang and Wenqiang Liu and Yan Zhang and Hanzhong Zhang and Chencan Fang and Le Qu and Xin Lu and Wentao Zhang and Nan Zhang and Aimin Jiang and Lingfeng Wu and Linhui Wang},
journal = {Translational oncology},
year = {2026},
month = oct,
doi = {10.1016/j.tranon.2026.103064},
url = {https://europepmc.org/article/MED/42860124},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A renal cyst-clear cell renal cell carcinoma comorbidity analysis identifies a FOXM1-positive epithelial COL6A1-CD44 axis that remodels fibroblasts.
AU - Hao Lv
AU - Chenyi Ge
AU - Yuming Jin
AU - Yu Fang
AU - Wenqiang Liu
AU - Yan Zhang
AU - Hanzhong Zhang
AU - Chencan Fang
AU - Le Qu
AU - Xin Lu
AU - Wentao Zhang
AU - Nan Zhang
AU - Aimin Jiang
AU - Lingfeng Wu
AU - Linhui Wang
PY - 2026
DA - 2026/10/11
JO - Translational oncology
DO - 10.1016/j.tranon.2026.103064
UR - https://europepmc.org/article/MED/42860124
AB - Background Renal cystic conditions are heterogeneous. We used a broad renal cyst-associated disease-gene framework to identify molecular programs shared with clear cell renal cell carcinoma (ccRCC), without modeling a specific cystic disorder or direct cyst-to-cancer progression.Methods We identified 237 shared genes between renal cyst disease and ccRCC (TCGA-KIRC), performed functional enrichment, Mendelian randomization, and built a random survival forest (RSF) risk score benchmarked against published signatures and immunotherapy cohorts. Single-cell (Scissor, SCENIC, scTenifoldKnk virtual FOXM1 knockout) and spatial transcriptomics (RCTD, CellChat) were integrated with fibroblast subclustering and oncoPredict drug screening. Candidate FOXM1 inhibitors were prioritized by docking and 100-ns molecular dynamics, with isovitexin validated functionally.Results The shared program was enriched for epithelial development and ECM remodeling. Two direction-specific Mendelian randomization analyses supported associations between genetic liability to kidney cancer and related renal cystic phenotypes. The RSF score showed robust prognostic discrimination across cohorts and separated immunotherapy outcomes. High-risk tumors were enriched for Tregs, B cells, and fibroblasts. FOXM1+ malignant epithelium represented the high-risk state, with elevated CNV burden and regulon activity; virtual FOXM1 knockout identified COL6A1 and CD44 among 129 significant non-target perturbation hits. Convergent single-cell and spatial analyses nominated a COL6A1-CD44 communication axis associated with fibroblast remodeling, with F5_SFRP2⁺ fibroblasts as the most plausible receiving state. These fibroblasts showed ECM-remodeling, adverse prognosis, and pathway activation. Isovitexin emerged as a lead FOXM1-targeting compound, significantly suppressing ccRCC proliferation, migration, and invasion.Conclusions These findings support a testable communication model involving FOXM1+ epithelium, COL6A1-CD44 and F5_SFRP2+ fibroblasts. The in vitro results also support further evaluation of isovitexin in ccRCC.
SN - 1936-5233
ER -