Abstract：
In acral melanoma (AM), progression from in situ (AMis) to invasive AM (iAM) leads to significantly reduced survival. However, evolutionary dynamics during this process remain elusive. Here, we report integrative molecular and spatial characterization of 147 AMs using genomics, bulk and single-cell transcriptomics, and spatial transcriptomics and proteomics. Vertical invasion from AMis to iAM displays an early and monoclonal seeding pattern. The subsequent regional expansion of iAM exhibits two distinct patterns, clonal expansion and subclonal diversification. Notably, molecular subtyping reveals an aggressive iAM subset featured with subclonal diversification, increased epithelial-mesenchymal transition (EMT), and spatial enrichment of APOE+/CD163+ macrophages. In vitro and ex vivo experiments further demonstrate that APOE+CD163+ macrophages promote tumor EMT via IGF1-IGF1R interaction. Adnexal involvement can predict AMis with higher invasive potential whereas APOE and CD163 serve as prognostic biomarkers for iAM. Altogether, our results provide implications for the early detection and treatment of AM.
摘要：
在肢端黑色素瘤（AM）中，从原位(AMis)进展到侵袭性AM(iAM)导致生存率显著降低.然而,在这个过程中的进化动力学仍然难以捉摸。这里,我们报告了使用基因组学对147个AMs进行的综合分子和空间表征，批量和单细胞转录组学，空间转录组学和蛋白质组学。从AMis到iAM的垂直入侵显示出早期和单克隆的播种模式。iAM随后的区域扩张表现出两种不同的模式，克隆扩展和亚克隆多样化。值得注意的是,分子亚型揭示了一个具有亚克隆多样化特征的积极的iAM子集，上皮-间质转化（EMT）增加，和APOE+/CD163+巨噬细胞的空间富集。体外和离体实验进一步证明APOE+CD163+巨噬细胞通过IGF1-IGF1R相互作用促进肿瘤EMT。附件受累可以预测具有较高侵袭潜力的AMis，而APOE和CD163可作为iAM的预后生物标志物。总之,我们的结果为AM的早期发现和治疗提供了启示.
