Liu Miao, Jin Shengyan, Agabiti Sherry S, Jensen Tyler B, Yang Tianqi, Radda Jonathan S D, Ruiz Christian F, Baldissera Gabriel, Rajaei Moein, Li Fang-Yong, Townsend Jeffrey P, Muzumdar Mandar Deepak, Wang Siyuan
Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
Nat Genet. 2025 Aug 18. doi: 10.1038/s41588-025-02297-w.
Although three-dimensional (3D) genome structures are altered in cancer, it remains unclear how these changes evolve and diversify during cancer progression. Leveraging genome-wide chromatin tracing to visualize 3D genome folding directly in tissues, we generated 3D genome cancer atlases of oncogenic Kras-driven mouse lung adenocarcinoma (LUAD) and pancreatic ductal adenocarcinoma. Here we define nonmonotonic, stage-specific alterations in 3D genome compaction, heterogeneity and compartmentalization as cancers progress from normal to preinvasive and ultimately to invasive tumors, discovering a potential structural bottleneck in early tumor progression. Remarkably, 3D genome architectures distinguish morphologic cancer states in single cells, despite considerable cell-to-cell heterogeneity. Analyses of genome compartmentalization changes not only showed that compartment-associated genes are more homogeneously regulated but also elucidated prognostic and dependency genes in LUAD, as well as an unexpected role for Rnf2 in 3D genome regulation. Our results highlight the power of single-cell 3D genome mapping to identify diagnostic, prognostic and therapeutic biomarkers in cancer.
尽管三维（3D）基因组结构在癌症中会发生改变，但目前尚不清楚这些变化在癌症进展过程中是如何演变和多样化的。利用全基因组染色质追踪技术直接在组织中可视化3D基因组折叠，我们生成了致癌性Kras驱动的小鼠肺腺癌（LUAD）和胰腺导管腺癌的3D基因组癌症图谱。在这里，我们定义了随着癌症从正常发展到侵袭前最终发展为侵袭性肿瘤，3D基因组压缩、异质性和区室化的非单调、阶段特异性改变，发现了早期肿瘤进展中的一个潜在结构瓶颈。值得注意的是，尽管细胞间存在相当大的异质性，但3D基因组结构能够区分单细胞中的形态学癌症状态。对基因组区室化变化的分析不仅表明与区室相关的基因受到更均匀的调控，还阐明了LUAD中的预后和依赖性基因，以及Rnf2在3D基因组调控中的意外作用。我们的结果突出了单细胞3D基因组图谱在识别癌症诊断、预后和治疗生物标志物方面的作用。
