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Updated: Sep 11, 2025
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Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening
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Tracing the evolution of single-cell 3D genomes in Kras-driven cancers
Miao Liu1, Shengyan Jin1, Sherry S Agabiti1,2
1Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
Nature Genetics
|August 18, 2025
Summary
Three-dimensional (3D) genome structures change during cancer progression. Single-cell 3D genome mapping reveals distinct cancer states and identifies potential biomarkers for lung adenocarcinoma and pancreatic ductal adenocarcinoma.
Area of Science:
- Genomics
- Cancer Biology
- Epigenetics
Background:
- Three-dimensional (3D) genome structure alterations are observed in cancer.
- The dynamic evolution of these structures during cancer progression is not well understood.
Purpose of the Study:
- To investigate the dynamic changes in 3D genome architecture during cancer progression.
- To create 3D genome cancer atlases for lung adenocarcinoma (LUAD) and pancreatic ductal adenocarcinoma.
- To identify potential diagnostic, prognostic, and therapeutic biomarkers.
Main Methods:
- Utilized genome-wide chromatin tracing for direct visualization of 3D genome folding in tissues.
- Generated single-cell 3D genome atlases for Kras-driven mouse LUAD and pancreatic ductal adenocarcinoma models.
- Analyzed stage-specific alterations in 3D genome compaction, heterogeneity, and compartmentalization.
Main Results:
- Discovered nonmonotonic, stage-specific changes in 3D genome compaction and compartmentalization during cancer progression.
- Identified a potential structural bottleneck in early tumor development.
- Demonstrated that 3D genome architectures can distinguish morphologic cancer states at the single-cell level.
- Found that compartment-associated genes exhibit more homogeneous regulation and identified prognostic/dependency genes in LUAD.
- Uncovered a novel role for Rnf2 in 3D genome regulation.
Conclusions:
- Single-cell 3D genome mapping provides powerful insights into cancer progression.
- 3D genome alterations are critical features that distinguish cancer states and heterogeneity.
- This approach can identify novel diagnostic, prognostic, and therapeutic targets in cancer.
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