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      Therapy Induced Genome Chaos: A Novel Mechanism of Rapid Cancer Drug Resistance

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          Most cited references58

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          Cancer drug resistance: an evolving paradigm.

          Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
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            Chromosomal instability drives metastasis through a cytosolic DNA response

            Chromosomal instability (CIN) is a hallmark of cancer and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-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 cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling. Genetic suppression of CIN significantly delays metastasis even in highly aneuploid tumor models, whereas inducing continuous chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumor cells co-opt chronic activation of innate immune pathways to spread to distant organs.
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              Tumour evolution inferred by single-cell sequencing.

              Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse 'pseudodiploid' cells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates. ©2011 Macmillan Publishers Limited. All rights reserved
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                10 June 2021
                2021
                : 9
                : 676344
                Affiliations
                [1] 1The Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan , Ann Arbor, MI, United States
                [2] 2Center for Molecular Medicine and Genomics, Wayne State University School of Medicine , Detroit, MI, United States
                [3] 3Department of Pathology, Wayne State University School of Medicine , Detroit, MI, United States
                Author notes

                Edited by: Dwayne G. Stupack, University of California, San Diego, United States

                Reviewed by: Joe Delaney, Medical University of South Carolina, United States; Olivier Harismendy, University of California, San Diego, United States

                *Correspondence: Jing Christine Ye jchrisy@ 123456med.umich.edu

                This article was submitted to Cell Death and Survival, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                10.3389/fcell.2021.676344
                8237085
                34195196
                6ee214ba-06bf-4f34-85a6-65ecc1d9a0a2
                Copyright © 2021 Ye, Horne, Zhang, Jackson and Heng.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 March 2021
                : 12 May 2021
                Page count
                Figures: 0, Tables: 1, Equations: 0, References: 58, Pages: 6, Words: 5063
                Categories
                Cell and Developmental Biology
                Opinion

                adaptive therapy,drug resistance,karyotype coding,non-clonal chromosome aberrations,polyploid giant cancer cells,two-phased cancer evolution,genome architecture theory,genome reorganization

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