Chromosomal instability promotes metastasis through a cytosolic DNA response
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE98183 | GEO | 2018/01/15
SECONDARY ACCESSION(S): PRJNA384217
REPOSITORIES: GEO
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Project description:Chromosomal instability (CIN) is a driver of cancer metastasis and immune evasion. Yet, the extent to which this effect depends on the immune system remains unknown. Here we show that CIN-induced chronic activation of the cGAS-STING pathway in cancer cells induces signal re-wiring downstream of STING, promoting a pro-metastatic tumor microenvironment (TME). Using ContactTracing, a newly developed, validated, and benchmarked tool to infer conditionally-dependent cell-cell interactions from single cell transcriptomic data, we identify a cancer cell-derived STING-dependent ER stress response that remodels a TME replete with immune suppressive myeloid cells and dysfunctional T cells. Simultaneously, CIN-induced chronic STING activation leads to interferon-specific tach-yphylaxis reinforcing immune suppression. Reversal of CIN, depletion of cancer cell STING, or inhibition of ER stress signaling upends CIN-dependent effects on the TME and suppresses metastasis in immune competent, but not severely immune compromised settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast, and colorectal cancer. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signaling, immune suppression, and metastasis in human triple-negative breast cancer; highlighting a viable strategy to identify and therapeutically intervene in tumors spurred by CIN-induced inflammation.
2023-06-20 | GSE189856 | GEO
Project description:Aneuploidy and chromosomal instability are both commonly found in cancer. Chromosomal instability leads to karyotype heterogeneity in tumors and is associated with therapy resistance, metastasis and poor prognosis. It has been hypothesized that aneuploidy per se is sufficient to drive CIN, however due to limited models and heterogenous results, it has remained controversial which aspects of aneuploidy can drive CIN. In this study we systematically tested the impact of different types of aneuploidies on the induction of CIN. We generated a plethora of isogenic aneuploid clones harboring whole chromosome or segmental aneuploidies in human p53-deficient RPE-1 cells. We observed increased segregation errors in cells harboring trisomies that strongly correlated to the number of gained genes. Strikingly, we found that clones harboring only monosomies do not induce a CIN phenotype. Finally, we found that an initial chromosome breakage event and subsequent fusion can instigate breakage-fusion-bridge cycles. By investigating the impact of monosomies, trisomies and segmental aneuploidies on chromosomal instability we further deciphered the complex relationship between aneuploidy and CIN.
2022-06-14 | GSE193437 | GEO
Project description:Chromosomal instability (CIN), defined as an increased occurrence of chromosome segregation errors during cell division, is a prominent form of genomic instability (Bakhoum and Avi Landau, 2017). It is the major cause of aneuploidy, an imbalanced complement of whole chromosomes or chromosome arms, which is the most prevalent genetic alteration in human cancers (Vasudevan et al., 2021; Santaguida and Amon, 2015). Importantly, aneuploidy is commonly associated with ongoing CIN through consecutive cell divisions (Shelzer et al. 2011; Passerini et al., 2016), resulting in intratumor genetic heterogeneity, a central driver of cancer evolution and therapeutic resistance (Sansregret et al., 2018; Ben-David and Amon, 2019). Indeed, aneuploidy has been shown to act both as a tumor suppressor and as a tumor initiator (Weaver et al., 2007; Silk et al., 2013; Vasudevan et al., 2020), most likely depending on the specific chromosomes that are gained or lost (Ben-David et al., 2011; Sack et al., 2018; Adell et al., 2023). Despite the ubiquitous presence of CIN in several aneuploid cancer types and its clinical relevance, its presence in B-cell acute lymphoblastic leukemia (B-ALL) remains largely unexplored owing to the impaired proliferation of leukemic cells in vitro and the lack of reliable experimental models to comprehensively assess chromosome segregation in vivo. B-ALL is the most frequent childhood cancer, with 75% of cases occurring in children under 6 years of age, and it is characterized by the accumulation of highly proliferative immature B-cell precursors in the bone marrow (BM) (Hunger and Mullighan, 2015). The presence of CIN and its contribution to aneuploid cB-ALL progression is largely unknown due to the lack of preclinical models to study actively dividing cells. Accordingly, studies of CIN in cB-ALL are limited to the characterization of chromosomal copy-number heterogeneity (chr-CNH) in primary cB-ALL samples, but there is controversy over its presence due to the different techniques used to assess karyotype variability (Raimondi et al., 1996; Talamo et al., 2010; Alpar et al., 2014; Heerema et al.; 2007; Ramos-Muntada et al., 2022). Here, we explored the presence and the levels of CIN in different clinically-relevant aneuploid subtypes of cB-ALL using single-cell whole-genome sequencing (WGS) of primary samples to reliably assess chr-CNH, and by generating a large cohort of PDX models from primary cB-ALL samples (cB-ALL-PDX). Our results in cB-ALL-PDX models revealed variable levels of CIN in aneuploid cB-ALL subtypes, which significantly correlate with intraclonal karyotype heterogeneity and with disease progression. Additionally, mass-spectrometry analyses of cB-ALL-PDX samples revealed a CIN “signature” enriched in mitosis and chromosome segregation regulatory pathways. We speculate that this signature identifies adaptive mechanisms to ongoing CIN in aneuploid cB-ALL cells, which displayed a transcriptional signature characterized by an impaired mitotic spindle as observed by RNA-sequencing (RNA-Seq) analyses of a large cohort of primary cB-ALL patient samples. Our work might help to improve stratification of patients with cB-ALL with different levels of CIN who could benefit in the future from new therapeutic approaches aiming to target ongoing CIN.
2023-09-15 | PXD042785 | Pride
Project description:Tumors that overexpress the MYC oncogene frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. Here, we identify that MYC overexpression induces defects in microtubule nucleation and mitotic spindle assembly, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in tumors. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.
2020-03-30 | GSE130921 | GEO
Project description:Tumors that overexpress the MYC oncogene frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. Here, we identify that MYC overexpression induces defects in microtubule nucleation and mitotic spindle assembly, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in tumors. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.
2020-03-30 | GSE130920 | GEO
Project description:STING molecule has been reported to be important adaptor molecule for cytosolic DNA sensing. We investigated gene expression by cytosolic DNA stimulation using bone marrow derived dendritic cells. We comparared gene expression profile between WT and STING knock out BMDCs after cytosolic DNA stimulation. We generated BMDCs by culturing in the presence of GM-CSF. BMDCs were stimulated by purified tumor-cell derived DNA using lipofectamine. After 7 hrs incubation, total RNA was isolated using Rneasy kit (Qiagen) and microarray was performed at genomic core facility in university of Chicago
2014-09-30 | E-GEOD-61835 | biostudies-arrayexpress
Project description:Chromosome-segregation errors in cancer cells are linked to chromosomal instability, the appearance of micronuclei and subsequent intracellular signaling events that drive cancer metastasis. The cause of these aberrations is not well-defined but a link to DNA-damage has been established. The Caspase-Activated DNAse (CAD) has been discovered for its role in the degradation of DNA in apoptotic cells but can also be activated in the absence of cell death. We here show that spontaneous CAD-activity drives chromosome missegregation, micronuclei generation, invasive growth and metastasis in human cancer cells. Genomic deletion of CAD reduced chromosome missegregation in mouse intestinal organoids as well as in tumor cells. CAD-deficient human cancer cells showed reduced migration, invasion and anchorage-independent growth in vitro as well as reduced metastatic potential in zebrafish and in mice. CAD-deficient cells displayed a substantially altered gene-expression profile, which overlapped with the profile of cells deficient in the Stimulator of Interferon Genes (STING). Multiple cancer signaling pathways were found to be regulated by CAD. A CAD-associated gene expression signature strongly predicted poor survival in cancer patients. These results identify CAD as a regulator of a signaling programme that determines cancer progression and prognosis.
2022-04-27 | GSE155493 | GEO
Project description:The DNA exonuclease TREX1 degrades endogenous cytosolic DNA. Cytosolic DNA triggers the cGAS/STING pathway which increases type I interferon. To investigate the physiological significance of TREX1 loss on in vivo tumor growth, we implanted control and TREX1-deficient CT26 tumor cells into immunocompetent BALB/c hosts.Tumor cells were collected 7 days after tumors reached around 200mm3.
2024-03-12 | E-MTAB-13816 | biostudies-arrayexpress
Project description:Chromosome segregation errors in oocytes lead to the production of aneuploid eggs, which are the leading cause of pregnancy loss and of several congenital diseases such as Down syndrome. The frequency of chromosome segregation errors in oocytes increases with maternal age, especially at a late stage of reproductive life. How aging at various life stages affects oocytes differently remains poorly understood. In this study, we describe aging-associated changes in the transcriptome profile of mouse oocytes throughout reproductive life. Our single-oocyte comprehensive RNA sequencing using RamDA-seq revealed that oocytes undergo transcriptome changes at a late reproductive stage, whereas their surrounding cumulus cells exhibit transcriptome changes at an earlier stage. Calorie restriction, a paradigm that reportedly prevents aging-associated egg aneuploidy, promotes a transcriptome shift in oocytes with the up-regulation of genes involved in chromosome segregation. This shift is accompanied by the improved maintenance of chromosomal cohesin, the loss of which is a hallmark of oocyte aging and causes chromosome segregation errors. These findings have implications for understanding how oocytes undergo aging-associated functional decline throughout their reproductive life in a context-dependent manner.
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Project description:Gene expression analysis of dsDNA90 stimulated human telomerase fibroblasts (hTERT-BJ1) after STING siRNA treatment. Genes whose expression that are affected by cytosolic DNA in a STING dependent manner will be identified and signaling pathways regulated by STING will be elucidated. hTERT-BJ1 cells were transfected with non-specific or STING siRNA for 72 hours followed by dsDNA90 stimulation for 3 hours. Total RNA was extracted for array analysis.
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