A unique genetic signature for cancer-associated fibroblasts in Melanoma metastases

Cancer-associated fibroblasts (CAFs) represent a central population of the tumor microenvironment (TME). Recently, single-cell RNA sequencing (scRNA-seq) analyes of primary tumors of different cancer entities yielded different classifications of CAF subsets underscoring heterogeneity of CAFs within the TME. Here, we analyzed the transcriptional signatures of approximately 8,400 CAFs and normal fibroblasts by scRNA-seq and compared genetic profiles of CAFs from murine melanoma primary tumors to CAFs from corresponding melanoma lung metastases. This revealed distinct subsets for primary tumor and metastasis specific CAF populations, respectively. Combined with spatial characterization of metastasis CAFs at the RNA and protein level, scRNA-analyses indicate a tumor-dependent crosstalk between neutrophils and CAFs, mediated via SAA3 and IL1b related signaling pathways, which can be recapitulated in vitro. Importantly, analyzing tissue sections of human patient samples this link was found to be present in human melanoma metastasis. Taken together, our data highlights unique characteristics of metastasis CAFs with potential therapeutic impact for melanoma metastasis.

癌症相关成纤维细胞（Cancer-associated fibroblasts, CAFs）是肿瘤微环境（tumor microenvironment, TME）的核心细胞群体。近年来，针对不同癌种原发性肿瘤开展的单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）分析得到了各异的CAF亚群分类方案，凸显了TME内CAFs的异质性。本研究通过scRNA-seq分析了约8400个CAFs及正常成纤维细胞的转录组特征，并将小鼠黑色素瘤原发性肿瘤来源的CAFs与对应黑色素瘤肺转移灶来源的CAFs的基因表达谱进行了比较。研究结果分别鉴定出了原发性肿瘤特异性与转移灶特异性的CAF亚群。结合转移灶CAFs在RNA及蛋白层面的空间表征分析，单细胞测序分析提示，中性粒细胞与CAFs之间存在肿瘤依赖性的细胞串扰，该串扰由SAA3及IL1β相关信号通路介导，且可在体外实验中重现。值得注意的是，对人类患者样本的组织切片进行分析后证实，这一信号关联在人类黑色素瘤转移灶中同样存在。综上，本研究数据揭示了黑色素瘤转移灶CAFs的独特生物学特征，其对黑色素瘤转移的临床干预或具有潜在治疗价值。