The recognition of DNA as an immune-stimulatory molecule is an evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. The cGAS-STING pathway was ...discovered as an important DNA-sensing machinery in innate immunity and viral defense. Recent advances have now expanded the roles of cGAS-STING to cancer. Highly aggressive, unstable tumors have evolved to co-opt this program to drive tumorigenic behaviors. In this review, we discuss the link between the cGAS-STING DNA-sensing pathway and antitumor immunity as well as cancer progression, genomic instability, the tumor microenvironment, and pharmacologic strategies for cancer therapy. SIGNIFICANCE: The cGAS-STING pathway is an evolutionarily conserved defense mechanism against viral infections. Given its role in activating immune surveillance, it has been assumed that this pathway primarily functions as a tumor suppressor. Yet, mounting evidence now suggests that depending on the context, cGAS-STING signaling can also have tumor and metastasis-promoting functions, and its chronic activation can paradoxically induce an immune-suppressive tumor microenvironment.
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.
Chromosomal instability is well recognized as a hallmark of many cancers and a driver of tumor evolution. In this Perspective, Bakhoum and Cantley discuss how this instability directly impacts the tumor micro-environment via cGAS and STING-dependent signaling.
Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers
, but whether they are mechanistically linked is unknown. Here we show that ...missegregation of mitotic chromosomes, their sequestration in micronuclei
and subsequent rupture of the micronuclear envelope
profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.
In this study, clonal hematopoiesis with somatic mutations was found in 10% of otherwise healthy people older than 65. The risk of hematologic cancer was substantially increased among these persons; ...in two cases, the subsequent cancer was related to the clone that predated the cancer.
The development of disease often involves dynamic processes that begin years or decades before the clinical onset. In many cases, however, the process of pathogenesis goes undetected until after the patient has symptoms and presents with clinically apparent disease.
Cancer arises owing to the combined effects of multiple somatic mutations, which are likely to be acquired at different times.
1
Early mutations may be present many years before disease develops. In some models of cancer development, early mutations lead to clonal expansions by stem cells or other progenitor cells.
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Such clonal expansions greatly increase the likelihood that later, cooperating mutations would . . .
The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has been primarily characterized as an inflammatory mechanism in higher eukaryotes in response to cytosolic ...double-stranded DNA (dsDNA). Since its initial discovery, detailed mechanisms delineating the dynamic subcellular localization of its different components and downstream signaling have been uncovered, leading to attempts to harness its proinflammatory properties for therapeutic benefit in cancer. Emerging evidence, however, indicates that a crucial primordial function of STING is to promote autophagy, and that downstream interferon (IFN) signaling emerged recently in its evolutionary history. Furthermore, studies suggest that this pathway is a crucial regulator of cellular metabolism that potentially couples inflammation to nutrient availability. We focus on the evolutionarily conserved functions of STING, and we discuss how a broader understanding of this pathway can help us to better appreciate its potential role in cancer and harness it for therapeutic benefit.
The cGAS–STING pathway is a crucial antiviral defense mechanism in mammalian cells.The role of cGAS–STING in cancer is complex because this pathway has been shown to exhibit both tumor-suppressive and tumor-promoting effects.Although STING was initially identified as a mediator of IFN signaling, recent studies have revealed that autophagy, and not IFN signaling, is a more highly conserved function in evolution.Mounting evidence suggests that STING signaling is complex and is dependent on interacting partners at the endoplasmic reticulum (ER).Disruption of STING signaling impacts on ER stress and unfolded protein responses, NF-κB signaling, and cellular metabolism.The IFN-independent functions of STING explain its tumor-promoting and prometastatic effects.
Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse ...subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events.
Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By ...integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.
Abstract Background context There is increasing scrutiny by several regulatory bodies regarding the complications of spine surgery. Precise delineation of the risks contributing to those ...complications remains a topic of debate. Purpose We attempted to create a predictive model of complications in patients undergoing spine surgery. Study design/setting Retrospective cohort study. Patient sample A total of 13,660 patients registered in the American College of Surgeons National Quality Improvement Project (NSQIP) database. Outcome measures Thirty-day postoperative risks of stroke, myocardial infarction, death, infection, urinary tract infection (UTI), deep vein thrombosis (DVT), pulmonary embolism (PE), and return to the operating room. Methods We performed a retrospective cohort study involving patients who underwent spine surgery between 2005 and 2010 and were registered in NSQIP. A model for outcome prediction based on individual patient characteristics was developed. Results Of the 13,660 patients, 2,719 underwent anterior approaches (19.9%), 565 corpectomies (4.1%), and 1,757 fusions (12.9%). The respective 30-day postoperative risks were 0.05% for stroke, 0.2% for MI, 0.25% for death, 0.3% for infection, 1.37% for UTI, 0.6% for DVT, 0.29% for PE, and 3.15% for return to the operating room. Multivariate analysis demonstrated that increasing age, more extensive operations (fusion, corpectomy), medical deconditioning (weight loss, dialysis, peripheral vascular disease, coronary artery disease, chronic obstructive pulmonary disease, diabetes), increasing body mass index, non-independent mobilization (preoperative neurologic deficit), and bleeding disorders were independently associated with a more than 3 days' length of stay. A validated model for outcome prediction based on individual patient characteristics was developed. The accuracy of the model was estimated by the area under the receiver operating characteristic curve, which was 0.95, 0.82, 0.87, 0.75, 0.74, 0.78, 0.76, 0.74, and 0.65 for postoperative risk of stroke, myocardial infarction, death, infection, DVT, PE, UTI, length of stay of 3 days or longer, and return to the operating room, respectively. Conclusions Our model can provide individualized estimates of the risks of postoperative complications based on preoperative conditions, and can potentially be used as an adjunct in decision-making for spine surgery.
SnapShot: CGAS-STING Signaling Galluzzi, Lorenzo; Vanpouille-Box, Claire; Bakhoum, Samuel F. ...
Cell,
03/2018, Letnik:
173, Številka:
1
Journal Article
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Odprti dostop
CGAS responds to cytosolic DNA by initiating a STING-dependent response that ultimately engages innate immune effectors to ensure the preservation of organismal homeostasis.
CGAS responds to ...cytosolic DNA by initiating a STING-dependent response that ultimately engages innate immune effectors to ensure the preservation of organismal homeostasis.
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