Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

Abstract

Chromosomal instability (CIN) is a pervasive feature of human cancers involved in tumor initiation and progression and which is found elevated in metastatic stages. CIN can provide survival and adaptation advantages to human cancers. However, too much of a good thing may come at a high cost for tumor cells as excessive degree of CIN-induced chromosomal aberrations can be detrimental for cancer cell survival and proliferation. Thus, aggressive tumors adapt to cope with ongoing CIN and most likely develop unique susceptibilities that can be their Achilles' heel. Determining the differences between the tumor-promoting and tumor-suppressing effects of CIN at the molecular level has become one of the most exciting and challenging aspects in cancer biology. In this review, we summarized the state of knowledge regarding the mechanisms reported to contribute to the adaptation and perpetuation of aggressive tumor cells carrying CIN. The use of genomics, molecular biology, and imaging techniques is significantly enhancing the understanding of the intricate mechanisms involved in the generation of and adaptation to CIN in experimental models and patients, which were not possible to observe decades ago. The current and future research opportunities provided by these advanced techniques will facilitate the repositioning of CIN exploitation as a feasible therapeutic opportunity and valuable biomarker for several types of human cancers.

Keywords: CIN; CIN adaptation; CIN tumors therapeutic vulnerabilities; Cancer; Metastasis; Therapy resistance.

Fig. 1

Diagram depicting human cells undergoing normal versus aberrant chromosome segregation that leads to CIN. Normal anaphase and cell division allows high fidelity separation of chromosomes between daughter cells and maintenance of genome stability and normal chromosomal content. Lagging DNA during anaphase can result in chromosome missegregation during cell division. Chromosomal instability (CIN) is the persistent rate of chromosome segregation errors every cell division in a cell population, CIN can be numerical which leads to unbalanced chromosome numbers or Aneuploidy, or structural in which results in damaged, broken, or rearranged chromosomes. CIN fuels the accumulation of further genomic changes promoting cancer progression, metastasis, and therapy resistance

Fig. 2

CIN proliferation barriers and mechanisms of adaptation in tumor cells. The diagram depicts reported mechanisms in the literature by which CIN tumor cell perpetuation can be prevented as well as the mechanisms of CIN adaptation in aggressive tumors. The classic tumor suppressor pathways are illustrated as potential roadblock for CIN cell continued proliferation. These pathways include but are not restricted to p53, Atm, and the Hippo pathway. Likewise, aneuploid cells can be eliminated by tumor cell extrinsic mechanisms involving NK cells. However, regardless of tumor suppressor status, metastatic tumors display increased CIN that correlates with high tumor heterogeneity and therapy resistance. Several mechanisms of adaptation are depicted including the reported finding of APC/C mutations that enhance fidelity of mitosis, transcriptional rewiring and upregulation of mitotic fidelity pathways controlled by MASTL kinase, upregulation of the cGAS-STING pathway in response to high CIN in metastasis, pro-survival pathways promoted by BCL9L mutations, and epigenetic reprogramming or upregulation of DNA damage repair (DDR). These and other emerging pathways continue to be heavily investigated in cancer