Chromosome Instability: Chaos from Within

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Chromosome Instability: Chaos from Within

RESEARCH HIGHLIGHTS Nature Reviews Cancer | AOP, published online 17 March 2011; doi:10.1038/nrc3048 CHROMOSOME INSTABILITY myosin light chain 2 showed that the internalized cells caused incom- plete formation of the contractile Chaos from within ring in the host cell, explaining why the cleavage furrow and cytokinesis Aneuploidy, the gain or loss of chro- host cell in the interim? In their latest were impeded. mosomes, is thought to primarily work, the authors examined cell- Tetraploidy is a common inter- on balance, arise from mutations that disrupt in-cell structures in primary cancer mediate of aneuploid cell lineages: entosis might be a mitosis or that alter centrosome samples and cell lines, and found that does this progression hold true numbers. However, routes to aneu- multinucleation of entosis host cells for these binucleated host cells? tumour-promoting ploidy might actually be more varied. was tenfold more common compared Fluorescence in situ hybridization for phenomenon Cell fusion has been suggested as an with adjacent single cells. chromosomes 8 and 12 revealed that alternative route, and a new study Time-lapse microscopy was binucleated intermediates of differ- proposes entosis as an important used to track immortalized or fully ent cell lines did produce aneuploid path to aneuploidy without a prior transformed breast and bronchial derivates. requirement for mutations. cell lines over many cell divisions. Confirming previous observa- Entosis was originally identi- This showed that entosis host cells tions, the authors found a positive fied by Michael Overholtzer and frequently failed to undergo cell correlation between cell-in-cell colleagues as a putative tumour- division, directly linking entosis frequency and advancing clinical suppressive mechanism, in which with multinucleation. Entosis host grade of tumour samples, indicating matrix-detached cells are internalized cells that did undergo mitosis that, on balance, entosis might be a into adjacent cells, resulting in cell- showed no disruptions of spindle tumour-promoting phenomenon. in-cell structures. Typically, internal- morphology or prophase to ana- Although entosis can be con- ized cells are eventually degraded to phase duration. However, when sidered as a non-genetic route to end their tumorigenic potential, but the internalized cell was by chance aneuploidy, it will be interesting to what are the consequences to the positioned as a physical barrier to determine whether there are indeed the plane of attempted cancer-relevant mutations that cleavage, failed cyto- predispose to entosis in addition kinesis and binucle- to those, such as the loss of TP53, ated, tetraploid that tolerate the resultant tetraploid cells resulted. Even state and drive its progression to partially internal- aneuploidy. ized cells were Darren J. Burgess found to serve as barriers to cyto- ORIGINAL RESEARCH PAPER Krajcovic, M. et al. A non-genetic route to aneuploidy in human kinesis. Staining cancers. Nature Cell Biol. 13, 324–330 (2011) for phosphorylated NATURE REVIEWS | CANCER VOLUME 11 | APRIL 2011 © 2011 Macmillan Publishers Limited. All rights reserved.

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Entosis Enables a Population Response to Starvation
www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 35), pp: 57934-57935 Editorial Entosis enables a population response to starvation Jens C. Hamann and Michael Overholtzer Commentary on: Hamann et al. Entosis is induced by glucose starvation. Cell Rep. 2017; 20:201-210. https://doi.org/10.1016/j. celrep.2017.06.037 Cell death isn’t just about apoptosis anymore. In cells in a population to scavenge extracellular nutrients and the last decade, numerous alternative mechanisms have accumulate the biomass necessary to support proliferation emerged, including regulated forms of necrosis, as well (Figure 1). Macropinocytosis has been shown to act as entosis, a unique mechanism that is executed as a cell similarly to allow cancer cells to scavenge extracellular murder rather than cell suicide [1]. Hamann et al. now proteins [5]. Entosis instead supplies bulk nutrients in identify glucose starvation as a key inducer of this non- the form of whole cells, where, on average, winner cells cell-autonomous form of cell death [2]. ingest two losers, providing a large nutrient supply that Cells that undergo entosis are killed as a result of is well suited to support the outgrowth of selected cells ingestion into their neighbors. They are not phagocytosed, in the population. Indeed, winners with ingested losers but rather form junctions with their neighbors and then have a nearly 10-fold proliferative advantage, and entosis invade into them, ultimately becoming killed through a is required for population re-growth during long-term mechanism involving autophagy proteins and lysosomal starvation. enzymes [1, 3]. This is a competitive process that results Our findings identify entosis as a population-scale in elimination of stiffer cells (“losers”) by softer ones starvation response with parallels to cell competition (“winners”), an effect linked to control over entotic cell occurring in developing tissues [6].
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G-Protein-Coupled Receptor Signaling and Polarized Actin Dynamics Drive
RESEARCH ARTICLE elifesciences.org G-protein-coupled receptor signaling and polarized actin dynamics drive cell-in-cell invasion Vladimir Purvanov, Manuel Holst, Jameel Khan, Christian Baarlink, Robert Grosse* Institute of Pharmacology, University of Marburg, Marburg, Germany Abstract Homotypic or entotic cell-in-cell invasion is an integrin-independent process observed in carcinoma cells exposed during conditions of low adhesion such as in exudates of malignant disease. Although active cell-in-cell invasion depends on RhoA and actin, the precise mechanism as well as the underlying actin structures and assembly factors driving the process are unknown. Furthermore, whether specific cell surface receptors trigger entotic invasion in a signal-dependent fashion has not been investigated. In this study, we identify the G-protein-coupled LPA receptor 2 (LPAR2) as a signal transducer specifically required for the actively invading cell during entosis. We find that 12/13G and PDZ-RhoGEF are required for entotic invasion, which is driven by blebbing and a uropod-like actin structure at the rear of the invading cell. Finally, we provide evidence for an involvement of the RhoA-regulated formin Dia1 for entosis downstream of LPAR2. Thus, we delineate a signaling process that regulates actin dynamics during cell-in-cell invasion. DOI: 10.7554/eLife.02786.001 Introduction Entosis has been described as a specialized form of homotypic cell-in-cell invasion in which one cell actively crawls into another (Overholtzer et al., 2007). Frequently, this occurs between tumor cells such as breast, cervical, or colon carcinoma cells and can be triggered by matrix detachment (Overholtzer et al., 2007), suggesting that loss of integrin-mediated adhesion may promote cell-in-cell invasion.
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Identification of Novel Potential Genes Involved in Cancer by Integrated
International Journal of Molecular Sciences Article Identiﬁcation of Novel Potential Genes Involved in Cancer by Integrated Comparative Analyses Francesco Monticolo 1, Emanuela Palomba 2 and Maria Luisa Chiusano 1,2,* 1 Department of Agricultural Sciences, Università Degli Studi di Napoli Federico II, 80055 Naples, Italy; [email protected] 2 Department of RIMAR, Stazione Zoologica “Anton Dohrn”, 80122 Naples, Italy; [email protected] * Correspondence: [email protected] Received: 26 October 2020; Accepted: 11 December 2020; Published: 15 December 2020 Abstract: The main hallmarks of cancer diseases are the evasion of programmed cell death, uncontrolled cell division, and the ability to invade adjacent tissues. The explosion of omics technologies offers challenging opportunities to identify molecular agents and processes that may play relevant roles in cancer. They can support comparative investigations, in one or multiple experiments, exploiting evidence from one or multiple species. Here, we analyzed gene expression data from induction of programmed cell death and stress response in Homo sapiens and compared the results with Saccharomyces cerevisiae gene expression during the response to cell death. The aim was to identify conserved candidate genes associated with Homo sapiens cell death, favored by crosslinks based on orthology relationships between the two species. Weidentified differentially-expressed genes, pathways that are significantly dysregulated across treatments, and characterized genes among those involved in induced cell death. We investigated on co-expression patterns and identified novel genes that were not expected to be associated with death pathways, that have a conserved pattern of expression between the two species. Finally, we analyzed the resulting list by HumanNet and identified new genes predicted to be involved in cancer.
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Classification of Cell Death
Cell Death and Differentiation (2009) 16, 3–11 & 2009 Macmillan Publishers Limited All rights reserved 1350-9047/09 $32.00 www.nature.com/cdd Review Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009 G Kroemer*,1,2,3, L Galluzzi1,2,3, P Vandenabeele4,5, J Abrams6, ES Alnemri7, EH Baehrecke8, MV Blagosklonny9, WS El-Deiry10, P Golstein11,12,13, DR Green14, M Hengartner15, RA Knight16, S Kumar17, SA Lipton18,19,20, W Malorni21, G Nun˜ez22, ME Peter23, J Tschopp24, J Yuan25, M Piacentini26,27, B Zhivotovsky28 and G Melino29,30 Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like ‘percentage apoptosis’ and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that ‘autophagic cell death’ is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including ‘entosis’, ‘mitotic catastrophe’, ‘necrosis’, ‘necroptosis’ and ‘pyroptosis’.
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Cell Death Responses to Nutrient Deprivation (2018)
CELL DEATH RESPONSES TO NUTRIENT DEPRIVATION By Jens Christian Hamann A Dissertation Presented to the Faculty of the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy New York, NY May 2018 Michael Overholtzer, Ph.D. Date Dissertation Mentor Copyright © 2018 by Jens Christian Hamann ii To my family, friends, and colleagues for their continued support. iii ABSTRACT Programmed cell death has traditionally been viewed as the induction of cell- autonomous suicide, but recent data suggest that cell death programs can also be activated non-cell autonomously. Among these, entosis, the process by which live neighboring cells are taken up by host cells and subsequently killed, occurs in human cancers and enables nutrient recovery from degraded neighbors. While the ability of entosis to provide nutrients to host cells has been established, whether nutrient withdrawal itself can induce this process is unknown. Here we identify glucose starvation as a potent inducer of entosis in both normal and tumor cell populations. We find that during glucose withdrawal, entotic cell uptake by winner cells is controlled by the energy-sensing kinase AMPK that is activated specifically within loser cells. We show that glucose starvation results in the appearance of two distinct cell populations based on their deformability, a characteristic that is predicted to result in high levels of entosis. Consistent with the model of AMPK controlling loser cell behavior, the appearance of less deformable, stiffer cells within the population is inhibited by blocking AMPK activity.
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Counteracting Genome Instability by P53-Dependent Mintosis
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.16.908954; this version posted January 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Title 2 Counteracting Genome Instability by p53-dependent Mintosis 3 4 Authors 5 Jianqing Liang1,6#, Zubiao Niu1#, Xiaochen Yu1#, Bo Zhang1,2, Manna Wang1,4, Banzhan Ruan1, 6 Hongquan Qin1,4, Xin Zhang1, You Zheng1, Songzhi Gu1, Xiaoyong Sai3, Yanhong Tai5, Lihua 7 Gao1, Li Ma4, Zhaolie Chen1, Hongyan Huang2*, Xiaoning Wang3*, Qiang Sun1* 8 9 Affiliations 10 1Laboratory of Cell Engineering, Institute of Biotechnology, 20 Dongda Street, Beijing 100071, P.R. 11 China. 12 2Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, 10 TIEYI Road, 13 Beijing 100038, P. R. China; 14 3National Clinic Center of Geriatric & the State Key Laboratory of Kidney, the Chinese PLA General 15 Hospital, Beijing 100853, P.R.China 16 4Institute of Molecular Immunology, Southern Medical University, Guangzhou 510515, P. R. China 17 5The 307 Hospital, 8 Dongda Street, Beijing 100071, P. R. China 18 6State Key Laboratory of Genetic Engineering, School of Life Science, Human Phenome Institute, 19 Fudan University, Shanghai, 200438, People's Republic of China. 20 21 *Correspondence to: 22 Qiang Sun 23 Email: [email protected] 24 Xiaoning Wang 25 Email: [email protected] 26 Hongyan Huang 27 Email: [email protected] 28 29 # These authors contributed equally to this work 30 31 Page 1 of 39 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.16.908954; this version posted January 16, 2020.
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Chromosomal Instability Versus Aneuploidy in Cancer
Opinion Difference Makers: Chromosomal Instability versus Aneuploidy in Cancer 1,2 1,2,3, Richard H. van Jaarsveld and Geert J.P.L. Kops * Human cancers harbor great numbers of genomic alterations. One of the most Trends common alterations is aneuploidy, an imbalance at the chromosome level. The majority of human tumors are Some aneuploid cancer cell populations show varying chromosome copy num- aneuploid and tumor cell populations undergo karyotype changes over time ber alterations over time, a phenotype known as ‘chromosomal instability’ (CIN). in vitro. An elevated rate of chromo- Chromosome segregation errors in mitosis are the most common cause for CIN some segregation errors [known as in vitro, and these are also thought to underlie the aneuploidies seen in clinical ‘chromosomal instability (CIN)’] is believed to underlie this. cancer samples. However, CIN and aneuploidy are different traits and they are likely to have distinct impacts on tumor evolution and clinical tumor behavior. In Besides ongoing mitotic errors, evolu- this opinion article, we discuss these differences and describe scenarios in tionary dynamics also impact on the karyotypic divergence in tumors. CIN which distinguishing them can be clinically relevant. can therefore not be inferred from kar- yotype measurement (e.g., in aneu- Aneuploidy and Chromosomal Instability in Cancer ploid tumors). The development of neoplastic lesions is accompanied by the accumulation of genomic CIN, aneuploidy, and karyotype diver- mutations [1]. Recent sequencing efforts greatly enhanced our understanding of cancer gence are three fundamentally different genomes and their evolution. These studies strongly suggest that elevated mutation rates traits, but are often equated in litera- combined with evolutionary dynamics ultimately ensure clonal expansion of tumor cells, giving ture, for example, to describe aneu- rise to heterogeneous tumors [2,3].
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G-Protein-Coupled Receptor Signaling and Polarized Actin Dynamics 2 Drive Cell-In-Cell Invasion
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HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Cell Rep Manuscript Author . Author manuscript; Manuscript Author available in PMC 2019 April 21. Published in final edited form as: Cell Rep. 2019 March 19; 26(12): 3212–3220.e4. doi:10.1016/j.celrep.2019.02.073. Entosis Controls a Developmental Cell Clearance in C. elegans Yongchan Lee1, Jens C. Hamann1,2, Mark Pellegrino3, Joanne Durgan4, Marie-Charlotte Domart5, Lucy M. Collinson5, Cole M. Haynes6, Oliver Florey4, and Michael Overholtzer1,2,7,8,* 1Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA 2Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 3Department of Biology, University of Texas Arlington, 500 UTA Blvd, Arlington, TX 76019, USA 4Signalling Programme, The Babraham Institute, Cambridge CB22 3AT, UK 5Electron Microscopy Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK 6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA 7BCMB Allied Program, Weill Cornell Medical College, New York, NY 10065, USA 8Lead Contact SUMMARY Metazoan cell death mechanisms are diverse and include numerous non-apoptotic programs. One program called entosis involves the invasion of live cells into their neighbors and is known to occur in cancers. Here, we identify a developmental function for entosis: to clear the male-specific linker cell in C. elegans. The linker cell leads migration to shape the gonad and is removed to facilitate fusion of the gonad to the cloaca.
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G C A T T A C G G C A T genes Perspective Micronuclei and Genome Chaos: Changing the System Inheritance Christine J. Ye 1,*, Zachary Sharpe 2, Sarah Alemara 2, Stephanie Mackenzie 2, Guo Liu 2, Batoul Abdallah 2, Steve Horne 2, Sarah Regan 2 and Henry H. Heng 2,3,* 1 The Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA 2 Center for Molecular Medicine and Genomics, Wayne State University School of Medicine, Detroit, MI 48201, USA; zasharpe@umﬂint.edu (Z.S.); [email protected] (S.A.); [email protected] (S.M.); [email protected] (G.L.); [email protected] (B.A.); [email protected] (S.H.); [email protected] (S.R.) 3 Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA * Correspondence: [email protected] (C.J.Y.); [email protected] (H.H.H.) Received: 3 March 2019; Accepted: 3 May 2019; Published: 13 May 2019 Abstract: Micronuclei research has regained its popularity due to the realization that genome chaos, a rapid and massive genome re-organization under stress, represents a major common mechanism for punctuated cancer evolution. The molecular link between micronuclei and chromothripsis (one subtype of genome chaos which has a selection advantage due to the limited local scales of chromosome re-organization), has recently become a hot topic, especially since the link between micronuclei and immune activation has been identiﬁed. Many diverse molecular mechanisms have been illustrated to explain the causative relationship between micronuclei and genome chaos.
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