The Multifaceted Role of Chromosomal Instability in Cancer and Its Microenvironment

Abstract

Chromosomal instability (CIN) is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. CIN results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. In addition to generating genomic heterogeneity that acts as a substrate for natural selection, CIN promotes inflammatory signaling by introducing double-stranded DNA into the cytosol, engaging the cGAS-STING anti-viral pathway. These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion.

Figure 1.. Chromosomal instability in cancer.

Multiple defects found in cancer can lead to both numerical and structural chromosomal abnormalities, which manifest as errors in chromosome segregation during mitosis. These errors lead to aneuploidy, karyotype heterogeneity, as well as the formation of micronuclei. Chromosomes enclosed in micronuclei are subjected to increased DNA damage and can become exposed to the cytoplasm after micronuclear envelope rupture. This mechanism has been proposed to promote massive structural chromosomal rearrangements, known as chromothripsis, the formation of extrachromosomal DNA as well as double minutes, which can be subjected to strong selective pressures and be present in hundreds of copies per cell. Furthermore, the presence of cytoplasmic double-stranded DNA (dsDNA) promotes inflammatory signaling through the activation of the cytosolic dsDNA sensing, cGAS-STING pathway.

Figure 2.. The multifaceted role of chromosomal instability (CIN) in cancer.

Chromosome missegregation can influence tumor evolution through the generation of genomic copy number heterogeneity that serves as the substrate for natural selection. In parallel, ongoing segregation errors can impart a variety of cellular stresses including transcriptional changes stemming from the leakage of genomic double-stranded DNA into the cytoplasm leading to inflammatory signaling. The multi-pronged effects of chromosome segregation enables genomic plasticity and supports tumor evolution, facilitating processes such as metastasis, immune evasion, and therapeutic resistance. In order to fully understand the consequences of CIN, one must first appreciate the diverse effects of chromosome missegregation on the tumor and its microenvironment.

Figure 3.. CIN activates cGAS-STING signaling.

Chromosome segregation errors lead to the formation of micronuclei, which often rupture in S-phase exposing double-stranded DNA (dsDNA) to the cytosol. The presence of cytosolic dsDNA activates the anti-viral cGAS-STING pathway which in normal cells promotes type I interferon production (A). Chromosomally unstable cancer cells however largely suppress type I interferon signaling through multiple mechanisms, yet they maintain the ability to exhibit alternative inflammatory STING-dependent signaling such as NF-κB (B). Chronic NF-κB activation has been shown to mediate the senescence-associated secretory phenotype (SASP) as well as cellular migration and metastasis.

Figure 4.. CGAS and TMEM173 (STING) are not frequently lost in cancer.

Oncoprints showing mutations and copy number alterations in CGAS, TMEM173, CDKN2A, and the interferon gene cluster in TCGA tumors. Most tumors maintain genomically intact copies of CGAS and TMEM173. A sizeable minority exhibits deep deletions in the interferon gene cluster on chromosome 9p suggesting a genetic mechanism for silencing type I interferon signaling in the presence of chronic cGAS-STING activation.

Figure 5.. Immune suppressive nature of CIN-induced inflammation.

Whereas most tumors retain functional copies of the cGAS and STING coding genes (A) tumor cells have been shown capable of suppressing type I interferon signaling through a variety of mechanisms (B). Chromosome segregation errors can promote chromosome 9p loss, which harbors the interferon gene cluster. Furthermore, they activate the p38 MAP-kinase pathway, which has been found to selectively inhibit ISG induction without affecting other STING-dependent inflammatory signaling, such as the SASP. Therefore, the consequences of cGAS-STING activation in cancer are context-dependent (C); acute STING activation in normal cells or near-diploid tumors is likely to exhibit an anti-tumor effect through the activation of type I interferon signaling, cellular senescence, and ensuing T-cell mediated immunity. As tumors become progressively chromosomally unstable, they adapt to tolerate chronic cGAS-STING signaling in response to cytosolic DNA by downregulating downstream interferon signaling and instead maintaining alternative pathways that promote tumorigenesis, senescence bypass, therapeutic resistance, and metastasis.

Figure 6.. An integrated approach to exploit CIN for a therapeutic benefit.

A viable adoption of CIN-directed therapies in the clinic must integrate a multi-disciplinary approach as well as careful patient selection. The widespread prevalence of CIN in advanced tumors offers an opportunity to devise therapeutic strategies that aim to target multi-drug resistance and metastatic progression. Furthermore, a better understanding of the mechanisms of CIN-induced inflammation might enable the development of novel approaches to augment anti-tumor immunity and synergize with existing immunotherapeutic agents used in the context of advanced metastatic disease.