The Experts below are selected from a list of 19653 Experts worldwide ranked by ideXlab platform
Samuel F. Bakhoum - One of the best experts on this subject based on the ideXlab platform.
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a cinful way to overcome addiction how Chromosomal Instability enables cancer to overcome its oncogene addiction
Embo Molecular Medicine, 2020Co-Authors: Daniel Bronder, Samuel F. BakhoumAbstract:Oncogene-addicted tumors present a valuable target for therapeutic intervention and an opportunity to achieve a wide therapeutic window. Nonetheless, resistance to targeted therapies is frequently observed and it arises through multiple mechanisms, including mutations in the target gene. Chromosomal Instability, a defining feature of human cancer, has been linked to targeted therapy resistance, but the mechanism underlying this association is poorly understood. In the current issue of EMBO Molecular Medicine, Salgueiro et al show that Chromosomal Instability can lead to the generation of alternative oncogenic drivers, thereby providing the ability for cancer cells to overcome the oncogene withdrawal bottleneck. Importantly, this study shows that, by generating de novo genomic diversity, Chromosomal Instability serves as an adaptive response to therapeutic insult.
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the multifaceted role of Chromosomal Instability in cancer and its microenvironment
Cell, 2018Co-Authors: Samuel F. Bakhoum, Lewis C CantleyAbstract: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.
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Chromosomal Instability drives metastasis through a cytosolic dna response
Nature, 2018Co-Authors: Samuel F. Bakhoum, Bryan Ngo, Ashley M Laughney, Julieann Cavallo, Charles J Murphy, Peter Ly, Pragya Shah, Roshan K SriramAbstract:Chromosomal Instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although Chromosomal Instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that Chromosomal Instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of Chromosomal Instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, Chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.
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Chromosomal Instability as a driver of tumor heterogeneity and evolution
Cold Spring Harbor Perspectives in Medicine, 2017Co-Authors: Samuel F. Bakhoum, Dan A LandauAbstract: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.
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Chromosomal Instability portends superior response of rectal adenocarcinoma to chemoradiation therapy
Cancer, 2014Co-Authors: Samuel F. Bakhoum, Bassem I Zaki, Arief A Suriawinata, Alan Eastman, Kristen M GarnerAbstract:BACKGROUND: Persistent chromosome segregation errors represent a conspicuous feature of human neoplasms. It is widely accepted that this Chromosomal Instability is associated with poor prognosis; however, its effect on therapeutic response is a matter of conjecture. METHODS: Here, the role of chromosome segregation errors in the response of patients with rectal adenocarcinoma to chemoradiation therapy (CRT) was examined. Pretreatment samples from 62 patients were surveyed for evidence of chromosome mis-segregation and mis-segregation frequency was correlated to the pathological response to CRT as determined by the tumor regression grade after surgical resection of irradiated tumors. RESULTS: Surprisingly, it was found that errors in chromosome segregation predicted enhanced pathological response of rectal adenocarcinoma to CRT (odds ratio, 3.9; P 5.02). Furthermore, tumor response inversely correlated with the frequency of cells that exhibited segregation errors during anaphase (correlation coefficient, 0.94; P <.05). Strikingly, elevated chromosome mis-segregation combined with decreased levels of the DNA damage repair protein Mre11 portended a markedly enhanced response (odds ratio, 54.0; P 5.008). CONCLUSIONS: The results of the current study demonstrate that Chromosomal Instability is a favorable predictor of response to CRT in patients with locally invasive rectal adenocarcinoma. Therefore, the authors propose that downstream structural damage to chromosomes resulting from segregation errors potentiates the effect of DNA-damaging therapies and synergizes with deficiencies in the DNA repair machinery. This work identifies a novel mechanistic marker that foretells treatment response to CRT and suggests that concomitant targeting of whole-chromosome segregation and DNA repair may constitute an effective therapeutic strategy. Cancer 2014;120:1733–42. V C 2014 American Cancer Society.
Holger Bastians - One of the best experts on this subject based on the ideXlab platform.
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increased microtubule assembly rates influence Chromosomal Instability in colorectal cancer cells
Nature Cell Biology, 2014Co-Authors: Norman Ertych, Ailine Stolz, Albrecht Stenzinger, Wilko Weichert, Silke Kaulfus, Peter Burfeind, Achim Aigner, Linda Wordeman, Holger BastiansAbstract:Chromosomal Instability (CIN) is a common feature of colorectal cancer cells and several mechanisms have been suggested for CIN generation. Bastians and colleagues find that increased microtubule plus-end stability can be triggered by AURKA overexpression and is associated with abnormal spindles and lagging chromosomes in colorectal cancer cells.
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increased microtubule assembly rates influence Chromosomal Instability in colorectal cancer cells
Nature Cell Biology, 2014Co-Authors: Norman Ertych, Ailine Stolz, Albrecht Stenzinger, Wilko Weichert, Silke Kaulfus, Peter Burfeind, Achim Aigner, Linda Wordeman, Holger BastiansAbstract:Chromosomal Instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms influencing CIN and its consequences on tumour growth are largely unknown. We identified an increase in microtubule plus-end assembly rates as a mechanism influencing CIN in colorectal cancer cells. This phenotype is induced by overexpression of the oncogene AURKA or by loss of the tumour suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and influencing CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumour growth in vitro and in vivo. Thus, we identify a fundamental mechanism influencing CIN in cancer cells and reveal its adverse consequence on tumour growth.
Zoltan Szallasi - One of the best experts on this subject based on the ideXlab platform.
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Chromosomal Instability confers intrinsic multidrug resistance
Cancer Research, 2011Co-Authors: Alvin J X Lee, Zoltan Szallasi, David Endesfelder, Andrew Rowan, Axel Walther, Nicolai Juul Birkbak, Andrew P Futreal, Julian Downward, Ian TomlinsonAbstract:Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote Chromosomal Instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models. Identification of distinct therapeutic agents that target tumor karyotypic complexity has important clinical implications. To identify distinct therapeutic approaches to specifically limit the growth of CIN tumors, we focused on a panel of colorectal cancer (CRC) cell lines, previously classified as either Chromosomally unstable (CIN(+)) or diploid/near-diploid (CIN(-)), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN(+) cell lines displayed significant intrinsic multidrug resistance compared with CIN(-) cancer cell lines, and this seemed to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multidrug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing Chromosomal heterogeneity and isogenic cell line models of CIN(+) displayed multidrug resistance relative to their CIN(-) parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN(+) predicted worse progression-free or disease-free survival relative to patients with CIN(-) disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity.
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targeting Chromosomal Instability and tumour heterogeneity in her2 positive breast cancer
Journal of Cellular Biochemistry, 2010Co-Authors: Rebecca A. Burrell, Charles Swanton, Nicolai Juul, Stephen R. D. Johnston, Zoltan Szallasi, Jorge S ReisfilhoAbstract:Chromosomal Instability (CIN) is a common cause of tumour heterogeneity and poor prognosis in solid tumours and describes cell-cell variation in chromosome structure or number across a tumour population. In this article we consider evidence suggesting that CIN may be targeted and may influence response to distinct chemotherapy regimens, using HER2-positive breast cancer as an example. Pre-clinical models have indicated a role for HER2 signalling in initiating CIN and defective cell-cycle control, and evidence suggests that HER2-targeting may attenuate this process. Anthracyclines and platinum agents may target tumours with distinct patterns of karyotypic complexity, whereas taxanes may have preferential activity in tumours with relative Chromosomal stability. A greater understanding of karyotypic complexity and identification of methods to directly examine and target CIN may support novel strategies to improve outcome in cancer.
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a signature of Chromosomal Instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers
Nature Genetics, 2006Co-Authors: Scott L Carter, Zoltan Szallasi, Aron Charles Eklund, Isaac S Kohane, Lyndsay HarrisAbstract:We developed a computational method to characterize aneuploidy in tumor samples based on coordinated aberrations in expression of genes localized to each Chromosomal region. We summarized the total level of Chromosomal aberration in a given tumor in a univariate measure termed total functional aneuploidy. We identified a signature of Chromosomal Instability from specific genes whose expression was consistently correlated with total functional aneuploidy in several cancer types. Net overexpression of this signature was predictive of poor clinical outcome in 12 cancer data sets representing six cancer types. Also, the signature of Chromosomal Instability was higher in metastasis samples than in primary tumors and was able to stratify grade 1 and grade 2 breast tumors according to clinical outcome. These results provide a means to assess the potential role of Chromosomal Instability in determining malignant potential over a broad range of tumors.
Charles Swanton - One of the best experts on this subject based on the ideXlab platform.
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determinants and clinical implications of Chromosomal Instability in cancer
Nature Reviews Clinical Oncology, 2018Co-Authors: Laurent Sansregret, Charles Swanton, Bart VanhaesebroeckAbstract:Aberrant Chromosomal architecture, ranging from small insertions or deletions to large Chromosomal alterations, is one of the most common characteristics of cancer genomes. Chromosomal Instability (CIN) underpins much of the intratumoural heterogeneity observed in cancers and drives phenotypic adaptation during tumour evolution. Thus, an urgent need exists to increase our efforts to target CIN as if it were a molecular entity. Indeed, CIN accelerates the development of anticancer drug resistance, often leading to treatment failure and disease recurrence, which limit the effectiveness of most current therapies. Identifying novel strategies to modulate CIN and to exploit the fitness cost associated with aneuploidy in cancer is, therefore, of paramount importance for the successful treatment of cancer. Modern sequencing and analytical methods greatly facilitate the identification and cataloguing of somatic copy-number alterations and offer new possibilities to better exploit the dynamic process of CIN. In this Review, we describe the principles governing CIN propagation in cancer and how CIN might influence sensitivity to immune-checkpoint inhibition, and survey the vulnerabilities associated with CIN that offer potential therapeutic opportunities.
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Cancer Chromosomal Instability: therapeutic and diagnostic challenges.
EMBO reports, 2012Co-Authors: Nicholas Mcgranahan, Rebecca A. Burrell, David Endesfelder, Marco Novelli, Charles SwantonAbstract:Chromosomal Instability (CIN)—which is a high rate of loss or gain of whole or parts of chromosomes—is a characteristic of most human cancers and a cause of tumour aneuploidy and intra-tumour heterogeneity. CIN is associated with poor patient outcome and drug resistance, which could be mediated by evolutionary adaptation fostered by intra-tumour heterogeneity. In this review, we discuss the clinical consequences of CIN and the challenges inherent to its measurement in tumour specimens. The relationship between CIN and prognosis supports assessment of CIN status in the clinical setting and suggests that stratifying tumours according to levels of CIN could facilitate clinical risk assessment.
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targeting Chromosomal Instability and tumour heterogeneity in her2 positive breast cancer
Journal of Cellular Biochemistry, 2010Co-Authors: Rebecca A. Burrell, Charles Swanton, Nicolai Juul, Stephen R. D. Johnston, Zoltan Szallasi, Jorge S ReisfilhoAbstract:Chromosomal Instability (CIN) is a common cause of tumour heterogeneity and poor prognosis in solid tumours and describes cell-cell variation in chromosome structure or number across a tumour population. In this article we consider evidence suggesting that CIN may be targeted and may influence response to distinct chemotherapy regimens, using HER2-positive breast cancer as an example. Pre-clinical models have indicated a role for HER2 signalling in initiating CIN and defective cell-cycle control, and evidence suggests that HER2-targeting may attenuate this process. Anthracyclines and platinum agents may target tumours with distinct patterns of karyotypic complexity, whereas taxanes may have preferential activity in tumours with relative Chromosomal stability. A greater understanding of karyotypic complexity and identification of methods to directly examine and target CIN may support novel strategies to improve outcome in cancer.
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Chromosomal Instability determines taxane response
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Charles Swanton, Alvin J X Lee, Aron Charles Eklund, Barbara Nicke, Marion Schuett, Thomas J Hardcastle, Rajat Roy, Philip East, Maik Kschischo, David EndesfelderAbstract:Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting Chromosomal Instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these “CIN-survival” genes is associated with poor outcome in estrogen receptor–positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in Chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents.
Norman Ertych - One of the best experts on this subject based on the ideXlab platform.
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increased microtubule assembly rates influence Chromosomal Instability in colorectal cancer cells
Nature Cell Biology, 2014Co-Authors: Norman Ertych, Ailine Stolz, Albrecht Stenzinger, Wilko Weichert, Silke Kaulfus, Peter Burfeind, Achim Aigner, Linda Wordeman, Holger BastiansAbstract:Chromosomal Instability (CIN) is a common feature of colorectal cancer cells and several mechanisms have been suggested for CIN generation. Bastians and colleagues find that increased microtubule plus-end stability can be triggered by AURKA overexpression and is associated with abnormal spindles and lagging chromosomes in colorectal cancer cells.
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increased microtubule assembly rates influence Chromosomal Instability in colorectal cancer cells
Nature Cell Biology, 2014Co-Authors: Norman Ertych, Ailine Stolz, Albrecht Stenzinger, Wilko Weichert, Silke Kaulfus, Peter Burfeind, Achim Aigner, Linda Wordeman, Holger BastiansAbstract:Chromosomal Instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms influencing CIN and its consequences on tumour growth are largely unknown. We identified an increase in microtubule plus-end assembly rates as a mechanism influencing CIN in colorectal cancer cells. This phenotype is induced by overexpression of the oncogene AURKA or by loss of the tumour suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and influencing CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumour growth in vitro and in vivo. Thus, we identify a fundamental mechanism influencing CIN in cancer cells and reveal its adverse consequence on tumour growth.