转移-侵袭级联描述了癌细胞从原发肿瘤成功扩散并最终在次要器官内生长所需的一系列步骤。尽管转移是一个动态的、多步骤的过程，但迄今为止大多数组学研究都集中于将原发性肿瘤与定义终末期疾病的转移性沉积物进行比较。这种静态方法意味着我们缺乏有关大多数肿瘤进展期间发生的基因组和表观基因组变化的信息。肿瘤进展的一个特别受研究的阶段是转移定植，在此期间细胞必须适应次要器官的新微环境。通过体内染色质可及性和基因表达的时间分析，我们识别了骨肉瘤肿瘤在肺微环境中形成和生长时发生的表观基因组的动态变化。此外，我们通过配对的体内和体外 CRISPR drop-out 筛选和药理学验证表明，上游转录因子代表了一类转移特异性依赖性基因。虽然当前模型将肺部定植描述为转移级联中的一个离散步骤，但我们的研究表明，它是通过多种表观遗传状态确定的轨迹，揭示了标准方法无法检测到的新治疗机会。© 2023。作者。

The metastasis-invasion cascade describes the series of steps required for a cancer cell to successfully spread from its primary tumor and ultimately grow within a secondary organ. Despite metastasis being a dynamic, multistep process, most omics studies to date have focused on comparing primary tumors to the metastatic deposits that define end-stage disease. This static approach means we lack information about the genomic and epigenomic changes that occur during the majority of tumor progression. One particularly understudied phase of tumor progression is metastatic colonization, during which cells must adapt to the new microenvironment of the secondary organ. Through temporal profiling of chromatin accessibility and gene expression in vivo, we identify dynamic changes in the epigenome that occur as osteosarcoma tumors form and grow within the lung microenvironment. Furthermore, we show through paired in vivo and in vitro CRISPR drop-out screens and pharmacological validation that the upstream transcription factors represent a class of metastasis-specific dependency genes. While current models depict lung colonization as a discrete step within the metastatic cascade, our study shows it is a defined trajectory through multiple epigenetic states, revealing new therapeutic opportunities undetectable with standard approaches.© 2023. The Author(s).