Background:Despite significant strides in anti-melanoma therapies, resistance and recurrence remain major challenges. A deeper understanding of the underlying biology of these challenges is necessary for developing more effective treatment paradigms.Methods:Melanoma single-cell data were retrieved from the Broad Single Cell Portal (SCP11). High-dimensional weighted gene co-expression network analysis (hdWGCNA), CellChat, and ligand-receptor relative crosstalk (RC) scoring were employed to evaluate intercellular and intracellular signaling. The prognostic value of key regulatory genes was assessed via Kaplan-Meier (KM) survival analysis using the ‘SKCM-TCGA’ dataset.Results:Twenty-seven (27) gene co-expression modules were identified via hdWGCNA. Notable findings include NRAS Q61L melanomas being enriched for modules involving C19orf10 and ARF4, while BRAF V600E melanomas were enriched for modules involvingALAS1andMYO1B. Additionally, CellChat analysis highlighted several dominant signaling pathways, namely MHC-II, CD99, and Collagen-receptor signaling, with numerous significant ligand-receptor interactions from melanocytes, including CD99-CD99 communications with cancer-associated fibroblasts, endothelial cells, NK cells, and T-cells. KM analysis revealed that higher expression ofSELL,BTLA,IL2RG,PDGFA,CLDN11,ITGB3, andSPNimproved overall survival, while higherFGF5expression correlated with worse survival. Protein-protein interaction network analysis further indicated significant interconnectivity among the identified prognostic genes.Conclusions:Overall, these insights underscore critical immune interactions and potential therapeutic targets to combat melanoma resistance, paving the way for more personalized and effective treatment strategies.
背景：尽管抗黑色素瘤疗法已取得显著进展，耐药性与复发仍是主要挑战。为建立更有效的治疗范式，需深入理解这些挑战背后的生物学机制。 方法：从Broad单细胞数据库（SCP11）获取黑色素瘤单细胞数据。采用高维加权基因共表达网络分析（hdWGCNA）、CellChat及配体-受体相对互作评分方法评估细胞间与细胞内信号传导。通过"SKCM-TCGA"数据集进行Kaplan-Meier生存分析，评估关键调控基因的预后价值。 结果：通过hdWGCNA鉴定出27个基因共表达模块。重要发现包括：NRAS Q61L突变型黑色素瘤富集于涉及C19orf10和ARF4的模块，而BRAF V600E突变型则富集于涉及ALAS1和MYO1B的模块。CellChat分析进一步揭示MHC-II、CD99及胶原受体信号通路为主导信号通路，其中黑色素细胞存在大量显著配体-受体互作，包括与癌症相关成纤维细胞、内皮细胞、NK细胞及T细胞的CD99-CD99通讯。生存分析显示SELL、BTLA、IL2RG、PDGFA、CLDN11、ITGB3和SPN高表达与总生存期改善相关，而FGF5高表达与不良预后相关。蛋白质互作网络分析表明这些预后基因存在显著互连关系。 结论：本研究揭示了对抗黑色素瘤耐药性的关键免疫互作机制与潜在治疗靶点，为开发更具个性化、更有效的治疗策略奠定基础。
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