文献类型：期刊文献

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

作者：Ma, Dongjing[1];Wang, Jinbin[1];Chen, Yicong[1];Yao, Ling[1];Wei, Qianya[1];Wu, Jianjun[1]

第一作者：Ma, Dongjing

通信作者：Wang, JB[1];Wu, JJ[1]

机构：[1]Gansu Univ Chinese Med, Sch Publ Hlth, Lanzhou 730000, Peoples R China

第一机构：甘肃中医药大学公共卫生学院

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Sch Publ Hlth, Lanzhou 730000, Peoples R China.|[10735e9d5e7087247e71b]甘肃中医药大学公共卫生学院;[10735]甘肃中医药大学;

年份：2026

卷号：58

期号：1

外文期刊名：ANNALS OF MEDICINE

收录：;Scopus(收录号：2-s2.0-105028929193);WOS:【SCI-EXPANDED(收录号:WOS:001674569200001)】；

基金：This work was supported by the National Natural Science Foundation of China (No. 82160900), the Gansu Province Joint Scientific Research Fund Major Project (24JRRA876), the Natural Science Foundation Youth Science and Technology Fund of Gansu Province (23JRRA1726) and the Gansu University of Traditional Chinese Medicine Talent Research Initiation Fund Project (2023YJRC-03).

语种：英文

外文关键词：Metastable state; chromosomal instability (CIN); replication stress (RS); cell cycle deregulation (CCD); therapy resistance

摘要：IntroductionCancer 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.DiscussionEvidence 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.ConclusionsThis 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.