Multi-omics characterization of CAF-related transcriptional programs reveals a smoking-context-informed 11-gene prognostic signature in HNSCC.
- 1Department of Otorhinolaryngology-Head and Neck Surgery, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, China.
- 2Department of Otorhinolaryngology-Head and Neck Surgery, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, China. [email protected].
Abstract
Background
Tobacco exposure contributes to the development and progression of head and neck squamous cell carcinoma (HNSCC) through genomic damage and alterations in the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are important stromal components of the tumor microenvironment, but the relationships among smoking background, CAF-related transcriptional programs, and clinical outcomes in HNSCC remain incompletely understood. We aimed to characterize CAF-related transcriptional programs in HNSCC and evaluate their prognostic relevance in the context of smoking status.Methods
We integrated scRNA-seq data with bulk RNA-seq analyses from TCGA-HNSC, in which smoking-background differential expression analyses were used for candidate-gene discovery. Using hdWGCNA, we identified CAF-associated gene modules and constructed a smoking-related CAF 11-gene (SRCAF-11) signature using machine-learning approaches. We evaluated the signature using external cohorts, immune deconvolution analyses, and SHAP-based feature interpretation. We also modulated INHBA expression in HNSCC cell lines to assess its effects on proliferation, migration, invasion, and EMT-related features.Results
We identified five transcriptionally distinct CAF subtypes. Matrix-remodeling CAFs (matCAFs) showed extracellular matrix-related features, and higher MuSiC-inferred matCAF relative abundance was associated with poorer survival. Smoker and non-smoker tumors did not differ significantly in MuSiC-inferred CAF-subtype proportions, whereas smoker tumors showed enrichment of EMT- and extracellular matrix-remodeling-related transcriptional programs. The SRCAF-11 signature stratified overall survival across retrospective HNSCC cohorts. INHBA emerged as a major contributor to the model and was preferentially expressed in matCAFs. High INHBA expression was associated with lower inferred immune activity and increased EMT-related transcriptional features in malignant epithelial cells. In vitro, modulation of INHBA expression altered HNSCC cell proliferation, migration, invasion, epithelial and mesenchymal marker expression, and E-cadherin localization.Conclusion
The SRCAF-11 signature showed prognostic stratification capability across retrospective HNSCC cohorts. INHBA was identified as a major model feature associated with p-EMT-related transcriptional characteristics. These findings support a context-dependent association between smoking status, CAF-related transcriptional programs, and aggressive tumor phenotypes in HNSCC. Further mechanistic and spatial validation is required.
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BibTeX
@article{shi2026multiomics,
title = {{Multi-omics characterization of CAF-related transcriptional programs reveals a smoking-context-informed 11-gene prognostic signature in HNSCC.}},
author = {Tao Shi and Yuqing Wang and Lisheng Yu and Yixin Zhao},
journal = {BMC cancer},
year = {2026},
month = aug,
doi = {10.1186/s12885-026-16603-0},
url = {https://europepmc.org/article/MED/42972293},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Multi-omics characterization of CAF-related transcriptional programs reveals a smoking-context-informed 11-gene prognostic signature in HNSCC.
AU - Tao Shi
AU - Yuqing Wang
AU - Lisheng Yu
AU - Yixin Zhao
PY - 2026
DA - 2026/08/05
JO - BMC cancer
DO - 10.1186/s12885-026-16603-0
UR - https://europepmc.org/article/MED/42972293
AB - Background Tobacco exposure contributes to the development and progression of head and neck squamous cell carcinoma (HNSCC) through genomic damage and alterations in the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are important stromal components of the tumor microenvironment, but the relationships among smoking background, CAF-related transcriptional programs, and clinical outcomes in HNSCC remain incompletely understood. We aimed to characterize CAF-related transcriptional programs in HNSCC and evaluate their prognostic relevance in the context of smoking status.Methods We integrated scRNA-seq data with bulk RNA-seq analyses from TCGA-HNSC, in which smoking-background differential expression analyses were used for candidate-gene discovery. Using hdWGCNA, we identified CAF-associated gene modules and constructed a smoking-related CAF 11-gene (SRCAF-11) signature using machine-learning approaches. We evaluated the signature using external cohorts, immune deconvolution analyses, and SHAP-based feature interpretation. We also modulated INHBA expression in HNSCC cell lines to assess its effects on proliferation, migration, invasion, and EMT-related features.Results We identified five transcriptionally distinct CAF subtypes. Matrix-remodeling CAFs (matCAFs) showed extracellular matrix-related features, and higher MuSiC-inferred matCAF relative abundance was associated with poorer survival. Smoker and non-smoker tumors did not differ significantly in MuSiC-inferred CAF-subtype proportions, whereas smoker tumors showed enrichment of EMT- and extracellular matrix-remodeling-related transcriptional programs. The SRCAF-11 signature stratified overall survival across retrospective HNSCC cohorts. INHBA emerged as a major contributor to the model and was preferentially expressed in matCAFs. High INHBA expression was associated with lower inferred immune activity and increased EMT-related transcriptional features in malignant epithelial cells. In vitro, modulation of INHBA expression altered HNSCC cell proliferation, migration, invasion, epithelial and mesenchymal marker expression, and E-cadherin localization.Conclusion The SRCAF-11 signature showed prognostic stratification capability across retrospective HNSCC cohorts. INHBA was identified as a major model feature associated with p-EMT-related transcriptional characteristics. These findings support a context-dependent association between smoking status, CAF-related transcriptional programs, and aggressive tumor phenotypes in HNSCC. Further mechanistic and spatial validation is required.
SN - 1471-2407
ER -