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

Liu, M.; Jin, S.; Agabiti, S. S.; Jensen, T. B.; Yang, T.; Radda, J. S. D.; Ruiz, C. F.; Baldissera, G.; Muzumdar, M. D.; Wang, S.

doi:10.1101/2023.07.23.550157

bioRxiv · 10.1101/2023.07.23.550157

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

Liu, M.·Jin, S.·Agabiti, S. S.·Jensen, T. B.·Yang, T.·Radda, J. S. D.·Ruiz, C. F.·Baldissera, G.·Muzumdar, M. D.·Wang, S.

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Abstract

Although three-dimensional (3D) genome structures are altered in cancer cells, little is known about 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 murine lung and pancreatic adenocarcinoma. Our data reveal stereotypical, non-monotonic, and stage-specific alterations in 3D genome folding heterogeneity, compaction, 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 histologic cancer states in single cells, despite considerable cell-to-cell heterogeneity. Gene-level analyses of evolutionary changes in 3D genome compartmentalization not only showed compartment-associated genes are more homogeneously regulated, but also elucidated prognostic and dependency genes in lung adenocarcinoma and a previously unappreciated role for polycomb-group protein Rnf2 in 3D genome regulation. Our results demonstrate the utility of mapping the single-cell cancer 3D genome in tissues and illuminate its potential to identify new diagnostic, prognostic, and therapeutic biomarkers in cancer.

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Liu, M., Jin, S., Agabiti, S. S., Jensen, T. B., Yang, T., Radda, J. S. D., Ruiz, C. F., Baldissera, G., Muzumdar, M. D., Wang, S.. 2023-07-24. A genome-wide single-cell 3D genome atlas of lung cancer progression. https://doi.org/10.1101/2023.07.23.550157

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