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<p>The molecular heterogeneity of brain metastases hampers therapeutic development for cures. To address this unmet and urgent need, we construct a comprehensive multi-omic, single cell, and spatially resolved atlas of 1,032 pan-cancer brain metastases, identifying four robust molecular subtypes with distinct biological programs and clinical associations. These brain metastases subtypes (BrMS) are defined by unique biological states: neural-like (BrMS1), metabolic (BrMS3), highly proliferative/immune-excluded (BrMS4), and an immune-infiltrated (BrMS2) state featuring a coordinated epithelial-mesenchymal transition program. Patient-derived organoids coupled with targeted drug screening indicate subtype-specific molecular dependencies and putative targets, notably mTOR signaling activation in BrMS3 and CDK4/6 axis activation in BrMS4, while BrMS1 and BrMS2 display distinct radiobiologic and immunologic signatures. This atlas provides a rigorous classification framework of BrMs and offers insights into subtype-specific molecular vulnerabilities.</p>

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A proteogenomic atlas of 1032 brain metastases identifies molecular subtypes, immune landscapes, and therapeutic vulnerabilities

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月26日

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  • Zhenyu Yang,
  • Shiyou Wei,
  • Hao Duan,
  • Xiuqi Wang,
  • Dainan Zhang,
  • Karrie Mei-Yee Kiang,
  • Yulan Deng,
  • Yuanzhong Yang,
  • Yin Ku,
  • Wanming Hu,
  • Chaowei Zou,
  • Meiqin Tang,
  • Yu Jiang,
  • Yu Liu,
  • Hongbin Lan,
  • Zexin Chen,
  • Gilberto Ka-Kit Leung,
  • Wang Jia,
  • Yonggao Mou,
  • Lunxu Liu,
  • Gao Zhang

摘要

The molecular heterogeneity of brain metastases hampers therapeutic development for cures. To address this unmet and urgent need, we construct a comprehensive multi-omic, single cell, and spatially resolved atlas of 1,032 pan-cancer brain metastases, identifying four robust molecular subtypes with distinct biological programs and clinical associations. These brain metastases subtypes (BrMS) are defined by unique biological states: neural-like (BrMS1), metabolic (BrMS3), highly proliferative/immune-excluded (BrMS4), and an immune-infiltrated (BrMS2) state featuring a coordinated epithelial-mesenchymal transition program. Patient-derived organoids coupled with targeted drug screening indicate subtype-specific molecular dependencies and putative targets, notably mTOR signaling activation in BrMS3 and CDK4/6 axis activation in BrMS4, while BrMS1 and BrMS2 display distinct radiobiologic and immunologic signatures. This atlas provides a rigorous classification framework of BrMs and offers insights into subtype-specific molecular vulnerabilities.