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

Miao Liu^#¹, Shengyan Jin^#¹, Sherry S Agabiti^#^{1

2}, Tyler B Jensen^{1

3}, Tianqi Yang¹, Jonathan S D Radda¹, Christian F Ruiz^{1

2}, Gabriel Baldissera¹, Moein Rajaei⁴, Fang-Yong Li^{5

6}, Jeffrey P Townsend^{4

6

7

8}, Mandar Deepak Muzumdar^{9

10

11

12

13

14

15

16}, Siyuan Wang^{17

18

19

20

21

22

23

24

25}

Affiliations

¹ Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
² Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
³ M.D.-Ph.D. Program, Yale University, New Haven, CT, USA.
⁴ Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA.
⁵ Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA.
⁶ Yale Cancer Center, Yale University, New Haven, CT, USA.
⁷ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
⁸ Program in Genetics, Genomics, and Epigenetics, Yale Cancer Center, Yale University, New Haven, CT, USA.
⁹ Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁰ Yale Cancer Biology Institute, Yale University, West Haven, CT, USA. mandar.muzumdar@yale.edu.
¹¹ M.D.-Ph.D. Program, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹² Yale Cancer Center, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹³ Program in Genetics, Genomics, and Epigenetics, Yale Cancer Center, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁴ Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁵ Yale Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁶ Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁷ Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
¹⁸ M.D.-Ph.D. Program, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
¹⁹ Yale Cancer Center, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²⁰ Yale Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²¹ Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²² Department of Cell Biology, Yale School of Medicine, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²³ Biochemistry, Quantitative Biology, Biophysics, and Structural Biology Program, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²⁴ Yale Center for RNA Science and Medicine, Yale School of Medicine, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²⁵ Yale Liver Center, Yale School of Medicine, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.

^# Contributed equally.

PMID: 40825871
DOI: 10.1038/s41588-025-02297-w

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

Miao Liu et al. Nat Genet. 2025.

. 2025 Aug 18.

doi: 10.1038/s41588-025-02297-w. Online ahead of print.

Authors

Affiliations

¹ Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
² Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
³ M.D.-Ph.D. Program, Yale University, New Haven, CT, USA.
⁴ Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA.
⁵ Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA.
⁶ Yale Cancer Center, Yale University, New Haven, CT, USA.
⁷ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
⁸ Program in Genetics, Genomics, and Epigenetics, Yale Cancer Center, Yale University, New Haven, CT, USA.
⁹ Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁰ Yale Cancer Biology Institute, Yale University, West Haven, CT, USA. mandar.muzumdar@yale.edu.
¹¹ M.D.-Ph.D. Program, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹² Yale Cancer Center, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹³ Program in Genetics, Genomics, and Epigenetics, Yale Cancer Center, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁴ Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁵ Yale Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁶ Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA. mandar.muzumdar@yale.edu.
¹⁷ Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
¹⁸ M.D.-Ph.D. Program, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
¹⁹ Yale Cancer Center, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²⁰ Yale Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²¹ Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²² Department of Cell Biology, Yale School of Medicine, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²³ Biochemistry, Quantitative Biology, Biophysics, and Structural Biology Program, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²⁴ Yale Center for RNA Science and Medicine, Yale School of Medicine, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.
²⁵ Yale Liver Center, Yale School of Medicine, Yale University, New Haven, CT, USA. siyuan.wang@yale.edu.

^# Contributed equally.

PMID: 40825871
DOI: 10.1038/s41588-025-02297-w

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: S.W., M.L., M.D.M., S.J. and S.S.A. are inventors on a patent applied for by Yale University related to this work. M.D.M. received research funding from a Genentech-supported AACR grant and an honorarium from Nested Therapeutics. S.W. is a co-inventor on a patent applied for by Harvard University related to MERFISH. The other authors declare no competing interests.

Update of

Tracing the evolution of single-cell cancer 3D genomes: an atlas for cancer gene discovery.
Liu M, Jin S, Agabiti SS, Jensen TB, Yang T, Radda JSD, Ruiz CF, Baldissera G, Rajaei M, Townsend JP, Muzumdar MD, Wang S. Liu M, et al. bioRxiv [Preprint]. 2024 Sep 9:2023.07.23.550157. doi: 10.1101/2023.07.23.550157. bioRxiv. 2024. Update in: Nat Genet. 2025 Aug 18. doi: 10.1038/s41588-025-02297-w. PMID: 37546882 Free PMC article. Updated. Preprint.

References

1. Zink, D., Fischer, A. H. & Nickerson, J. A. Nuclear structure in cancer cells. Nat. Rev. Cancer 4, 677–687 (2004). - PubMed
1. Krijger, P. H. L. & de Laat, W. Regulation of disease-associated gene expression in the 3D genome. Nat. Rev. Mol. Cell Biol. 17, 771–782 (2016). - PubMed
1. Zheng, H. & Xie, W. The role of 3D genome organization in development and cell differentiation. Nat. Rev. Mol. Cell Biol. 20, 535–550 (2019). - PubMed
1. Yu, M. & Ren, B. The three-dimensional organization of mammalian genomes. Annu. Rev. Cell Dev. Biol. 33, 265–289 (2017). - PubMed - PMC
1. Bickmore, W. A. & van Steensel, B. Genome architecture: domain organization of interphase chromosomes. Cell 152, 1270–1284 (2013). - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous