School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China.
School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu, 730000, China.
Comput Biol Med. 2023 Dec;167:107597. doi: 10.1016/j.compbiomed.2023.107597. Epub 2023 Oct 18.
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.
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.
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.
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.
癌症相关成纤维细胞（CAFs）在肿瘤侵袭和转移中起着关键作用。然而，关于皮肤黑色素瘤（CM）中 CAF 标志物的研究仍然很少。本研究旨在探讨 CM 中潜在的 CAF 标志物，提出潜在的治疗靶点，为 CM 中 CAFs 的靶向治疗提供新的见解。
我们利用加权基因共表达网络分析识别 CM 中的 CAF 特征基因，并对这些基因建立的 CAF 风险评分进行全面的生物信息学分析。此外，利用单细胞测序分析、空间转录组分析和细胞实验验证特征基因的表达和分布模式。进一步利用分子对接筛选潜在的靶向药物。
筛选出 FBLN1 和 COL5A1 这两个关键的 CAF 特征基因，建立 CAF 风险评分。随后，对 CAF 风险评分进行全面的生物信息学分析，结果表明高风险评分组在与肿瘤进展相关的途径中显著富集。此外，CAF 风险评分与 CM 患者的临床预后、免疫治疗反应和肿瘤突变负荷显著负相关。此外，通过多组学分析和实验验证，进一步鉴定 FBLN1 和 COL5A1 为 CM 中的 CAF 特异性标志物。最终，基于这两个靶点，筛选出米非司酮和地塞米松作为潜在的抗 CAFs 药物。
研究结果表明，FBLN1 和 COL5A1 是 CM 中的 CAF 特征基因，与 CM 的进展、治疗和预后有关。对 CAF 特征基因的全面探索有望为 CM 的临床治疗提供新的思路。
