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Chromosomal instability (CIN) is an intricate phenomenon that is often found in human cancer, characterized by persisting errors in chromosome segregation. This ongoing chromosome mis-segregation results in structural and numerical chromosomal abnormalities that have been widely described to promote tumor evolution. In addition to being a driver of tumor evolution, recent evidence demonstrates CIN to be the central node of the crosstalk between a tumor and its surrounding microenvironment, as mediated by the cGAS-STING pathway. The role that cGAS-STING signaling exerts on CIN tumors is both complex and paradoxical. On one hand, the cGAS-STING axis promotes the clearance of CIN tumors through recruitment of immune cells, thus suppressing tumor progression. On the other hand, the cGAS-STING pathway has been described to be the major regulator in the promotion of metastasis of CIN tumors. Here, we review this dual role of the cGAS-STING pathway in the context of chromosomal instability and discuss the potential therapeutic implications of cGAS-STING signaling for targeting CIN tumors.

Many cancers possess an incorrect number of chromosomes, a state described as aneuploidy. Aneuploidy is often caused by Chromosomal Instability (CIN), a process of continuous chromosome mis-segregation. CIN is believed to endow tumours with enhanced evolutionary capabilities due to increased intratumour heterogeneity, and facilitating adaptive resistance to therapies. Recently, however, additional consequences and associations with CIN have been revealed, prompting the need to understand this universal hallmark of cancer in a multifaceted context. This review is focused on the investigation of possible links between CIN, metastasis and the host immune system in cancer development and treatment. We specifically focus on these links since most cancer deaths are due to the consequences of metastasis, and immunotherapy is a rapidly expanding novel avenue of cancer therapy.

Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications—doublings of the entire complement of chromosomes—are linked to genetic instability and frequently found in human cancers 1 – 3 . It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis 4 – 8 ; however, the immediate consequences of tetraploidy in the first interphase are not known. This is a key question because single whole-genome duplication events such as cytokinesis failure can promote tumorigenesis 9 and DNA double-strand breaks 10 . Here we find that human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization. Extensive DNA damage occurs during the first interphase following induction of tetraploidy in human cells, largely as a result of the lower amount of protein relative to DNA.

Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells with structural chromosomal abnormalities that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures are upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors. Chromosomal instability leads to aneuploidy, a state of karyotype imbalance. By inducing controlled chromosome mis-segregation, Santaguida and colleagues show that aneuploidy can also instigate chromosomal instability.

Copy number variations (CNVs), the gain or loss of genomic regions, are associated with disease, especially cancer. Single cell technologies offer new possibilities to capture within-sample heterogeneity of CNVs and identify subclones relevant for tumor progression and treatment outcome. Several computational tools have been developed to identify CNVs from scRNA-seq data. However, an independent benchmarking of them is lacking. Here, we evaluate six popular methods in their ability to correctly identify ground truth CNVs, euploid cells and subclonal structures in 21 scRNA-seq datasets. We discover dataset-specific factors influencing the performance, including dataset size, the number and type of CNVs in the sample and the choice of the reference dataset. Methods which include allelic information perform more robustly for large droplet-based datasets, but require higher runtime. Furthermore, the methods differ in their additional functionalities. We offer a benchmarking pipeline to identify the optimal method for new datasets, and improve methods’ performance. Several computational tools have now been developed to identify copy number variations (CNVs) from scRNA-seq data. Here authors benchmark these methods, showing that performance is affected by dataset quality, CNV type and reference dataset, with methods including allelic information being more robust in large datasets.

Centrosome amplification is a feature of cancer cells associated with chromosome instability and invasiveness. Enhancing chromosome instability and subsequent cancer cell death via centrosome unclustering and multipolar divisions is an aimed-for therapeutic approach. Here, we show that centrosome amplification potentiates responses to conventional chemotherapy in addition to its effect on multipolar divisions and chromosome instability. We perform single-cell live imaging of chemotherapy responses in epithelial ovarian cancer cell lines and observe increased cell death when centrosome amplification is induced. By correlating cell fate with mitotic behaviors, we show that enhanced cell death can occur independently of chromosome instability. We identify that cells with centrosome amplification are primed for apoptosis. We show they are dependent on the apoptotic inhibitor BCL-XL and that this is not a consequence of mitotic stresses associated with centrosome amplification. Given the multiple mechanisms that promote chemotherapy responses in cells with centrosome amplification, we assess such a relationship in an epithelial ovarian cancer patient cohort. We show that high centrosome numbers associate with improved treatment responses and longer overall survival. Our work identifies apoptotic priming as a clinically relevant consequence of centrosome amplification, expanding our understanding of this pleiotropic cancer cell feature.

Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis 1 . CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING 2 , 3 . These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer 4 , and, although they have been implicated in metastasis 5 , it is not known why loss-of-function mutations do not arise in primary tumours 4 . Here we show that inactivation of cGAS–STING signalling selectively impairs the survival of triple-negative breast cancer cells that display CIN. CIN triggers IL-6–STAT3-mediated signalling, which depends on the cGAS–STING pathway and the non-canonical NF-κB pathway. Blockade of IL-6 signalling by tocilizumab, a clinically used drug that targets the IL-6 receptor (IL-6R), selectively impairs the growth of cultured triple-negative breast cancer cells that exhibit CIN. Moreover, outgrowth of chromosomally instable tumours is significantly delayed compared with tumours that do not display CIN. Notably, this targetable vulnerability is conserved across cancer types that express high levels of IL-6 and/or IL-6R in vitro and in vivo. Together, our work demonstrates pro-tumorigenic traits of cGAS–STING signalling and explains why the cGAS–STING pathway is rarely inactivated in primary tumours. Repurposing tocilizumab could be a strategy to treat cancers with CIN that overexpress IL-6R. The survival of cells with chromosomal instability (CIN) depends on the cGAS–STING pathway, in which IL-6 and its receptor have a key role; this vulnerability can be exploited to treat tumours that display CIN.

Centrosome amplification is a feature of cancer cells associated with chromosome instability and invasiveness. Enhancing chromosome instability and subsequent cancer cell death via centrosome unclustering and multipolar divisions is an aimed-for therapeutic approach. Here we show that centrosome amplification favors responses to conventional chemotherapy independently of multipolar divisions and chromosome instability. We perform single-cell live imaging of chemotherapy responses in epithelial ovarian cancer cell lines and observe increased cell death when centrosome amplification is induced. By correlating cell fate with mitotic behaviors, we show that enhanced cell death occurs independently of chromosome instability. We identify that cells with centrosome amplification are primed for apoptosis. We show they are dependent on the apoptotic inhibitor BCL-XL, and that this is not a consequence of mitotic stresses associated with centrosome amplification. Given the multiple mechanisms that promote chemotherapy responses in cells with centrosome amplification, we assess such a relationship in an epithelial ovarian cancer patient cohort. We show that high centrosome numbers associate with improved chemotherapy responses and longer overall survival. Our work identifies apoptotic priming as a clinically relevant consequence of centrosome amplification, expanding our understanding of this pleiotropic cancer cell feature.