Integrative molecular and spatial analysis reveals evolutionary dynamics and tumor-immune interplay of in situ and invasive acral melanoma

Cancer Cell. 2024 Jun 10;42(6):1067-1085.e11. doi: 10.1016/j.ccell.2024.04.012. Epub 2024 May 16.


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.

Keywords: APOE; CD163; acral melanoma; genomic instability; intratumor heterogeneity; molecular subtype; spatial omics; tumor evolution; tumor-associated macrophage.

MeSH terms

  • Aged
  • Antigens, CD* / genetics
  • Antigens, CD* / metabolism
  • Antigens, Differentiation, Myelomonocytic* / genetics
  • Antigens, Differentiation, Myelomonocytic* / metabolism
  • Apolipoproteins E / genetics
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Disease Progression
  • Epithelial-Mesenchymal Transition* / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Melanoma* / genetics
  • Melanoma* / immunology
  • Melanoma* / pathology
  • Middle Aged
  • Neoplasm Invasiveness*
  • Prognosis
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Receptors, Cell Surface
  • Skin Neoplasms* / genetics
  • Skin Neoplasms* / immunology
  • Skin Neoplasms* / pathology
  • Spatial Analysis
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology


  • Antigens, Differentiation, Myelomonocytic
  • Antigens, CD
  • CD163 antigen
  • Apolipoproteins E
  • ApoE protein, human
  • Receptor, IGF Type 1
  • Biomarkers, Tumor
  • Receptors, Cell Surface