Identification and targeting of cancer-associated fibroblast signature genes for prognosis and therapy in Cutaneous melanoma

Guokun Zhang; Pengfei Ji; Peng Xia; Haoyun Song; Zhao Guo; Xiaohui Hu; Yanan Guo; Xinyi Yuan; Yanfeng Song; Rong Shen; Degui Wang

doi:10.1016/j.compbiomed.2023.107597

Identification and targeting of cancer-associated fibroblast signature genes for prognosis and therapy in Cutaneous melanoma

Comput Biol Med. 2023 Dec:167:107597. doi: 10.1016/j.compbiomed.2023.107597. Epub 2023 Oct 18.

Authors

Guokun Zhang¹, Pengfei Ji², Peng Xia³, Haoyun Song⁴, Zhao Guo⁵, Xiaohui Hu⁶, Yanan Guo⁷, Xinyi Yuan⁸, Yanfeng Song⁹, Rong Shen¹⁰, Degui Wang¹¹

Affiliations

¹ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: zhanggk21@lzu.edu.cn.
² School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: 220220926751@lzu.edu.cn.
³ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: xiap21@lzu.edu.cn.
⁴ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: songhy20@lzu.edu.cn.
⁵ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: guozh2015@lzu.edu.cn.
⁶ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: 120220905771@lzu.edu.cn.
⁷ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: guoyn2021@lzu.edu.cn.
⁸ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: 220220926460@lzu.edu.cn.
⁹ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: songyanfeng@lzu.edu.cn.
¹⁰ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China. Electronic address: shenr@lzu.edu.cn.
¹¹ School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu, 730000, China. Electronic address: wangdegui@lzu.edu.cn.

PMID: 37875042
DOI: 10.1016/j.compbiomed.2023.107597

Abstract

Background: Cancer-associated fibroblasts (CAFs) play pivotal roles in tumor invasion and metastasis. However, studies on CAF biomarkers in Cutaneous Melanoma (CM) are still scarce. This study aimed to explore the potential CAF biomarkers in CM, propose the potential therapeutic targets, and provide new insights for targeted therapy of CAFs in CM.

Methods: We utilized weighted gene co-expression network analysis to identify CAF signature genes in CM, and conducted comprehensive bioinformatics analysis on the CAF risk score established by these genes. Moreover, single-cell sequencing analysis, spatial transcriptome analysis, and cell experiments were utilized for verifying the expression and distribution pattern of signature genes. Furthermore, molecular docking was employed to screen potential target drugs.

Results: FBLN1 and COL5A1, two crucial CAF signature genes, were screened to establish the CAF risk score. Subsequently, a comprehensive bioinformatic analysis of the CAF risk score revealed that high-risk score group was significantly enriched in pathways associated with tumor progression. Besides, CAF risk score was significantly negatively correlated with clinical prognosis, immunotherapy response, and tumor mutational burden in CM patients. In addition, FBLN1 and COL5A1 were further identified as CAF-specific biomarkers in CM by multi-omics analysis and experimental validation. Eventually, based on these two targets, Mifepristone and Dexamethasone were screened as potential anti-CAFs drugs.

Conclusion: The findings indicated that FBLN1 and COL5A1 were the CAF signature genes in CM, which were associated with the progression, treatment, and prognosis of CM. The comprehensive exploration of CAF signature genes is expected to provide new insight for clinical CM therapy.

Keywords: Bioinformatics; Cancer-associated fibroblasts; Cutaneous melanoma; Therapeutic target; Tumor immune microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Cancer-Associated Fibroblasts* / metabolism
Cancer-Associated Fibroblasts* / pathology
Humans
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma, Cutaneous Malignant
Molecular Docking Simulation
Skin Neoplasms* / drug therapy
Skin Neoplasms* / genetics

Substances

Biomarkers, Tumor