耶鲁大学王思远课题组近日取得一项新成果。经过不懈努力，他们发现了在Kras驱动的癌症中追踪单细胞3D基因组的进化。相关论文于2025年8月18日发表在《自然—遗传学》杂志上。

利用全基因组染色质追踪技术直接可视化组织中的三维基因组折叠，课题组研究人员生成了致癌Kras驱动的无主题肺腺癌（LUAD）和胰腺导管腺癌的三维基因组癌症图谱。

在这里，该课题组定义了癌症从正常到侵袭前，最终到侵袭性肿瘤的过程中，三维基因组压实、异质性和区区化的非单调性、阶段特异性改变，发现了早期肿瘤进展的潜在结构瓶颈。值得注意的是，尽管细胞间存在相当大的异质性，但3D基因组结构在单个细胞中区分了形态癌症状态。对基因组区室化变化的分析不仅表明区室相关基因的调控更加均匀，而且还阐明了LUAD的预后和依赖基因，以及Rnf2在3D基因组调控中的意想不到的作用。他们的研究结果突出了单细胞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力量。

据介绍，尽管三维（3D）基因组结构在癌症中发生了改变，但在癌症进展过程中这些变化是如何演变和多样化的仍不清楚。

附：英文原文

Title: Tracing the evolution of single-cell 3D genomes in Kras-driven cancers

Author: 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

Issue&Volume: 2025-08-18

Abstract: 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.

DOI: 10.1038/s41588-025-02297-w

Source: https://www.nature.com/articles/s41588-025-02297-w