表观基因组
表观遗传学
转移
表观遗传学
生物
骨肉瘤
染色质
原发性肿瘤
肿瘤微环境
转录组
癌症研究
静脉注射
DNA甲基化
计算生物学
癌症
基因表达
基因
肿瘤细胞
遗传学
作者
William Pontius,Ellen S. Hong,Zachary J Faber,Jeremy Gray,Craig D. Peacock,Ian Bayles,Katreya Lovrenert,Cynthia F. Bartels,Peter C. Scacheri
出处
期刊:Research Square - Research Square
日期:2022-11-16
标识
DOI:10.21203/rs.3.rs-2199384/v1
摘要
Abstract 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.
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