A genome-wide single-cell 3D genome atlas of lung cancer progression

Miao Liu, Shengyan Jin, Sherry S. Agabiti, Tyler B. Jensen, Tianqi Yang, Jonathan S. D. Radda, Christian F. Ruiz, Gabriel Baldissera, Mandar Deepak Muzumdar, Siyuan Wang
bioRxiv (2023)


Alterations in three-dimensional (3D) genome structures are associated with cancer15. However, how genome folding evolves and diversifies during subclonal cancer progression in the native tissue environment remains unknown. Here, we leveraged a genome-wide chromatin tracing technology to directly visualize 3D genome folding in situ in a faithful Kras-driven mouse model of lung adenocarcinoma (LUAD)6, generating the first single-cell 3D genome atlas of any cancer. We discovered stereotypical 3D genome alterations during cancer development, including a striking structural bottleneck in preinvasive adenomas prior to progression to LUAD, indicating a stringent selection on the 3D genome early in cancer progression. We further showed that the 3D genome precisely encodes cancer states in single cells, despite considerable cell-to-cell heterogeneity. Finally, evolutionary changes in 3D genome compartmentalization – partially regulated by polycomb group protein Rnf2 through its ubiquitin ligase-independent activity – reveal novel genetic drivers and suppressors of LUAD progression. Our results demonstrate the importance of mapping the single-cell cancer 3D genome and the potential to identify new diagnostic and therapeutic biomarkers from 3D genomic architectures.