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Inverse Game Theory Characterizes Frequency-Dependent Selection Driven by Karyotypic Diversity in Triple Negative
Thomas Veith1,2, Richard Beck1, Joel S Brown1,3
1Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
Biorxiv : the Preprint Server for Biology
|April 8, 2025
Summary
Chromosomal instability drives cancer evolution. Our new framework, ECO-K, analyzes genetic diversity in cancer cells to predict how subpopulations interact, revealing new therapeutic targets.
Area of Science:
- Cancer Biology
- Genomics
- Evolutionary Biology
Background:
- Chromosomal instability (CIN) and copy number alterations (CNAs) are hallmarks of cancer, driving tumor progression and therapeutic resistance.
- Intratumoral genetic heterogeneity arises from CNAs, leading to distinct subpopulations that interact and influence tumor evolution via frequency-dependent selection.
Purpose of the Study:
- To introduce ECO-K (Ecological-Karyotypes), an inverse game theory framework.
- To infer subpopulation interactions from longitudinal single-cell whole genome sequencing data.
- To identify frequency-dependent selection dynamics in cancer driven by karyotypic diversity.
Main Methods:
- Development of the ECO-K inverse game theory framework.
- Application of ECO-K to serially-passaged triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs).
- Analysis of longitudinal single-cell whole genome sequencing data to infer ecological dynamics.
Main Results:
- Systematic identification of frequency-dependent selection dynamics governed by karyotypic diversity.
- Discovery of karyotypically defined subpopulations acting as interaction hubs in one PDX lineage.
- Association of interaction hubs with specific chromosomal alterations (chromosome 1 loss, chromosome 14p gain).
Conclusions:
- The ECO-K framework provides testable predictions of intratumoral ecological dynamics.
- Understanding subpopulation interactions is crucial for disrupting tumor evolution.
- Targeting key subpopulations offers strategic opportunities for cancer therapy.
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