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<p>Melanomas are genetically heterogeneous, displaying mitogen-activated protein kinase mutations and homozygous loss of tumor suppressor genes. Mouse models combining such mutations produce fast-growing tumors. In contrast, rare, slow-growing tumors arise in mice combining <i>Braf</i> activation with heterozygous loss of <i>Pten</i>. Here we show that similar tumors can arise in albino mice bearing only a <i>Braf</i> mutation. Incidence kinetics suggest a stochastic event underlies tumorigenesis in tumors that arise with only a <i>Braf</i> mutation, yet de novo mutations or structural variants that could explain the incidence of most tumors could not be found. Single-cell transcriptomics of tumors identify a cell type resembling “neural crest-like” cells in human and mouse melanomas. These exist in normal mouse skin, expand upon <i>Braf</i> activation, and persist through serial transplantation; analyses of gene expression suggest they serve as precursors of malignant cells. This state may serve as an intermediate on a slow path to malignancy that may provide a diagnostically and therapeutically important source of cellular heterogeneity.</p>

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Uncovering minimal pathways in melanoma initiation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月26日

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  • Hui Xiao,
  • Jessica Shiu,
  • Chi-Fen Chen,
  • Jie Wu,
  • Peijie Zhou,
  • Sahil S. Telang,
  • Rolando Ruiz-Vega,
  • Robert A. Edwards,
  • Qing Nie,
  • Arthur D. Lander,
  • Anand K. Ganesan

摘要

Melanomas are genetically heterogeneous, displaying mitogen-activated protein kinase mutations and homozygous loss of tumor suppressor genes. Mouse models combining such mutations produce fast-growing tumors. In contrast, rare, slow-growing tumors arise in mice combining Braf activation with heterozygous loss of Pten. Here we show that similar tumors can arise in albino mice bearing only a Braf mutation. Incidence kinetics suggest a stochastic event underlies tumorigenesis in tumors that arise with only a Braf mutation, yet de novo mutations or structural variants that could explain the incidence of most tumors could not be found. Single-cell transcriptomics of tumors identify a cell type resembling “neural crest-like” cells in human and mouse melanomas. These exist in normal mouse skin, expand upon Braf activation, and persist through serial transplantation; analyses of gene expression suggest they serve as precursors of malignant cells. This state may serve as an intermediate on a slow path to malignancy that may provide a diagnostically and therapeutically important source of cellular heterogeneity.