# A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability

## TL;DR

This review introduces a new framework for understanding how cancer evolves by linking replication stress, cell cycle issues, and chromosomal instability.

## Contribution

The paper proposes the RS–CCD–CIN axis as a systems-level model for cancer evolution.

## Key findings

- RS, CCD, and CIN form an interconnected network that drives tumor heterogeneity and adaptability.
- Targeting multiple components of the RS–CCD–CIN axis may improve cancer therapy outcomes.
- Single-cell profiling reveals variability in RS, CCD, and CIN states within tumors.

## Abstract

Cancer cell proliferation occurs within the context of persistent genomic instability. In this review, we propose the RS–CCD–CIN axis as a systems-level framework in which replication stress (RS), cell cycle deregulation (CCD) and chromosomal instability (CIN) form an interdependent triad that shapes tumour evolution. This axis represents a constrained metastable state in which genomic instability is tolerated and buffered. The objective of this review is to synthesize the current understanding of how the RS–CCD–CIN axis contributes to tumour heterogeneity, adaptability and therapy response.

Evidence indicates that RS, CCD and CIN operate as a dynamic, interconnected network rather than as independent processes. Replication stress induces DNA damage and mutagenesis, while partial checkpoint disruption permits cells with unresolved lesions to proliferate. Chromosomal instability generates both structural and numerical alterations, contributing to intratumoural heterogeneity. Together, these processes facilitate adaptation to environmental and therapeutic pressures. Extrachromosomal DNA, micronuclei formation and cytosolic DNA signalling, including the cGAS–STING pathway, connect genomic instability to adaptive responses and immune modulation. Single-cell and spatial profiling reveal temporal and spatial variability in RS, CCD and CIN states, highlighting the limitations of static biomarkers. Therapeutically, targeting individual components often yields limited durability, whereas approaches that simultaneously perturb multiple aspects of the RS–CCD–CIN axis may improve clinical outcomes.

This review highlights the RS–CCD–CIN axis as a fragile and metastable architecture that supports cancer evolution, while also being susceptible to collapse. A deeper understanding of this interconnected framework may inform the development of therapeutic strategies and enhance the management of resistance.