Tracing the evolution of single-cell cancer 3D genomes: an atlas for cancer gene discovery

• DOI: 10.1101/2023.07.23.550157
• Publication Date: 2023-07-24T22:55:11Z
• Authors: Miao Liu; Shengyan Jin; Sherry S. Agabiti; Tyler B. Jensen; Tianqi Yang; Jonathan S. D. Radda; Christian F. Ruiz; Gabriel Baldissera; Moein Rajaei; Jeffrey P. Townsend; Mandar Deepak Muz...; Siyuan Wang
• Keywords: Article; 3. Good health

AbstractAlthough 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.