Construction of cancer- associated fibroblasts related risk signature based on single-cell RNA-seq and bulk RNA-seq data in bladder urothelial carcinoma

Yunxun Liu; Jun Jian; Ye Zhang; Lei Wang; Xiuheng Liu; Zhiyuan Chen

doi:10.3389/fonc.2023.1170893

Construction of cancer- associated fibroblasts related risk signature based on single-cell RNA-seq and bulk RNA-seq data in bladder urothelial carcinoma

Front Oncol. 2023 Apr 14:13:1170893. doi: 10.3389/fonc.2023.1170893. eCollection 2023.

Authors

Yunxun Liu^{1

2}, Jun Jian^{1

2}, Ye Zhang^{1

2}, Lei Wang^{1

2}, Xiuheng Liu^{1

2}, Zhiyuan Chen^{1

2}

Affiliations

¹ Department of Urology, Renmin Hospital, Wuhan University, Wuhan, China.
² Institute of Urologic Disease, Renmin Hospital, Wuhan University, Wuhan, China.

Abstract

Background: The ability of cancer-associated fibroblasts (CAFs) to encourage angiogenesis, tumor cell spread, and increase treatment resistance makes them pro-tumorigenic. We aimed to investigate the CAF signature in Bladder urothelial carcinoma (BLCA) and, for clinical application, to build a CAF-based risk signature to decipher the immune landscape and screen for suitable treatment BLCA samples.

Methods: CAF-related genes were discovered by superimposing CAF marker genes discovered from single-cell RNA-seq (scRNA-seq) data taken from the GEO database with CAF module genes discovered by weighted gene co-expression network analysis (WGCNA) using bulk RNA-seq data from TCGA. After identifying prognostic genes related with CAF using univariate Cox regression, Lasso regression was used to build a risk signature. With microarray data from the GEO database, prognostic characteristics were externally verified. For high and low CAF-risk categories, immune cells and immunotherapy responses were analyzed. Finally, a nomogram model based on the risk signature and prospective chemotherapeutic drugs were examined.

Results: Combining scRNA-seq and bulk-seq data analysis yielded a total of 124 CAF-related genes. LRP1, ANXA5, SERPINE2, ECM1, RBP1, GJA1, and FKBP10 were the seven BLCA prognostic genes that remained after univariate Cox regression and LASSO regression analyses. Then, based on these genes, prognostic characteristics were created and validated to predict survival in BLCA patients. Additionally, risk signature had a strong correlation with known CAF scores, stromal scores, and certain immune cells. The CAF-risk signature was identified as an independent prognostic factor for BLCA using multifactorial analysis, and its usefulness in predicting immunotherapy response was confirmed. Based on risk classification, we projected six highly sensitive anticancer medicines for the high-risk group.

Conclusion: The prognosis of BLCA may be accurately predicted using CAF-based risk signature. With a thorough understanding of the BLCA CAF-signature, it might be able to explain the BLCA patients' response to immunotherapy and identify a potential target for BLCA treatment.

Keywords: bladder urothelial carcinoma; cancer-associated fibroblasts; immunotherapy; prognosis; single-cell RNA-seq; tumor microenvironment.

Grants and funding

This study was supported by the National Natural Science Foundation of China (no. 81972408) and the National Natural Science Foundation of China (no. 82000639).