Critical Fragility Emerges from Chromosomal Instability in Cancer
- 1University of Padova
Abstract
Genomic instability is a major driver of tumor evolution, promoting diversification and adaptation while simultaneously increasing the accumulation of deleterious alterations. How tumor populations balance these opposing effects remains poorly understood. Here, we introduce a computational framework that explicitly represents diploid genomes, functional gene classes, point mutations, and chromosome-segregation errors in spatially constrained and well-mixed tumor populations. We identify a viability boundary separating sustained tumor expansion from instability-induced population collapse. Within the viable regime, mutation and selection generate a stable distribution of genomic-instability classes that is accurately captured by an analytical replicator--mutator description. Near the viability boundary, tumor dynamics exhibit prolonged extinction transients and strong sensitivity to stochastic fluctuations, with important differences between solid and liquid architectures. Chromosomal alterations further modify growth by creating transient benefits through increased gene dosage and genetic redundancy, while ultimately increasing genomic fragility. Finally, simulated interventions show that eliminating low-instability subpopulations or increasing the global mutational burden can displace tumors beyond their viability boundary and trigger irreversible collapse. These results identify genome instability as both an evolutionary advantage and an intrinsic vulnerability, providing a quantitative framework for developing therapies that exploit the limits of tumor evolution.
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BibTeX
@misc{zambelli2026critical,
title = {{Critical Fragility Emerges from Chromosomal Instability in Cancer}},
author = {F. Zambelli and G. D'Addese and Q. Marti-Baena and J. Sardanyes and G. Aguade-Gorgorio and R. Sole},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.748208},
url = {https://www.biorxiv.org/content/10.64898/2026.08.31.748208v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Critical Fragility Emerges from Chromosomal Instability in Cancer
AU - F. Zambelli
AU - G. D'Addese
AU - Q. Marti-Baena
AU - J. Sardanyes
AU - G. Aguade-Gorgorio
AU - R. Sole
PY - 2026
DA - 2026/08/31
PB - bioRxiv
DO - 10.64898/2026.08.31.748208
UR - https://www.biorxiv.org/content/10.64898/2026.08.31.748208v1
AB - Genomic instability is a major driver of tumor evolution, promoting diversification and adaptation while simultaneously increasing the accumulation of deleterious alterations. How tumor populations balance these opposing effects remains poorly understood. Here, we introduce a computational framework that explicitly represents diploid genomes, functional gene classes, point mutations, and chromosome-segregation errors in spatially constrained and well-mixed tumor populations. We identify a viability boundary separating sustained tumor expansion from instability-induced population collapse. Within the viable regime, mutation and selection generate a stable distribution of genomic-instability classes that is accurately captured by an analytical replicator--mutator description. Near the viability boundary, tumor dynamics exhibit prolonged extinction transients and strong sensitivity to stochastic fluctuations, with important differences between solid and liquid architectures. Chromosomal alterations further modify growth by creating transient benefits through increased gene dosage and genetic redundancy, while ultimately increasing genomic fragility. Finally, simulated interventions show that eliminating low-instability subpopulations or increasing the global mutational burden can displace tumors beyond their viability boundary and trigger irreversible collapse. These results identify genome instability as both an evolutionary advantage and an intrinsic vulnerability, providing a quantitative framework for developing therapies that exploit the limits of tumor evolution.
ER -