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

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

  • Cancer Cell. 2024 May 16:S1535-6108(24)00136-3. doi: 10.1016/j.ccell.2024.04.012.
Hengkang Liu 1 Jiawen Gao 2 Mei Feng 3 Jinghui Cheng 3 Yuchen Tang 4 Qi Cao 3 Ziji Zhao 3 Ziqiao Meng 3 Jiarui Zhang 4 Guohong Zhang 4 Chong Zhang 4 Mingming Zhao 4 Yicen Yan 4 Yang Wang 4 Ruidong Xue 5 Ning Zhang 6 Hang Li 7
Affiliations

Affiliations

  • 1 Peking University-Yunnan Baiyao International Medical Research Center, Peking University First Hospital, Beijing 100191, China; School of Basic Medical Sciences, International Cancer Institute, Peking University, Beijing 100191, China.
  • 2 National Clinical Research Center for Skin and Immune Diseases, NMPA Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Peking University First Hospital, Beijing 100034, China; Institute of Photomedicine and Department of Phototherapy at Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China.
  • 3 Peking University-Yunnan Baiyao International Medical Research Center, Peking University First Hospital, Beijing 100191, China.
  • 4 National Clinical Research Center for Skin and Immune Diseases, NMPA Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Peking University First Hospital, Beijing 100034, China.
  • 5 Peking University-Yunnan Baiyao International Medical Research Center, Peking University First Hospital, Beijing 100191, China; School of Basic Medical Sciences, International Cancer Institute, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 6 Peking University-Yunnan Baiyao International Medical Research Center, Peking University First Hospital, Beijing 100191, China; School of Basic Medical Sciences, International Cancer Institute, Peking University, Beijing 100191, China; Yunnan Baiyao Group, Kunming 650500, China. Electronic address: [email protected].
  • 7 Peking University-Yunnan Baiyao International Medical Research Center, Peking University First Hospital, Beijing 100191, China; National Clinical Research Center for Skin and Immune Diseases, NMPA Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Peking University First Hospital, Beijing 100034, China; Yunnan Baiyao Group, Kunming 650500, China. Electronic address: [email protected].
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.

Keywords

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

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