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Advances in Genome Regulation in Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 30765

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Special Issue Editors

Dr. Jekaterina Erenpreisa

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Chief Guest Editor

Latvian Biomedical Research and Study Centre, LV1067 Riga, Latvia
Interests: cancer biology; cancer resistance; cancer polyploidy and aneuploidy; parasexual processes in cancer; cancer evolution; systems biology; genome organization

Prof. Dr. Mark Steven Cragg

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Guest Editor

Centre for Cancer Immunology, University of Southampton, Southampton SO16 6YD, UK
Interests: antibody immunotherapy; antibody therapeutics; Fc gamma receptors; tumour microenvironment

Prof. Dr. Alessandro Giuliani

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Guest Editor

Environment and Health Department, Istituto Superiore di Sanità, 00161 Rome, Italy
Interests: data analysis; complex systems; systems biology; statistical mechanics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The last decade has seen significant advances in our understanding of how the cancer genome is regulated. Following the detailed genetic blueprints arising from the Human Genome Project and consequent Cancer Genome Sequencing Projects, the somatic mutation theory of cancer has become challenged, leading to questions about the rationale for precision oncology [1]. Concurrently, more detailed appreciation of the biological complexity of cancer [2] and cancer-related gene interactions are converging with systems-wide, bioinformatic approaches to better understand the ‘physics of complexity’ [3]. After losing the “war on cancer” we have to recognise that cancer is inherently and secondarily resistant to many treatments and to question why [4]. Recent progress indicates that the human cellular networks have specific “cancer attractors” that evolved during macroevolution and adaptation of cellular organisms to hostile environments [5, 6]. Such, “survival at the brink” of extinction appears enabled by explorative adaptation - competition and oscillations between opposing genome/proteome network states and epigenetic cell fates [7]. Chaotic genome regulation, including via transposons, may help explain cancer aneuploidy and resistance to treatments [8].

Despite this rapid progress, many questions remain. Are there constraints on the degree of chaos? Can cancer progression continue solely as a result of genomic instability, which perpetually increases aneuploidy? Can these processes ensure cancer cell immortality? Do they arrive at some point at the Weismann law of heredity transfer between generations of organisms [7]? Can a cancer cell really undergo reversible soma-to-germ reprogramming and behave like a single organism with a “life-cycle” [9]? Is one of the keys to this conundrum hidden in the germline genes ectopically expressed in cancer and associated with poor survival [10]? Are these same genes involved in ensuring genome order or do they multiply and compound its errors?

Original articles and reviews addressing these essential questions are invited. The potential authors are encouraged to send an Abstract to the Guest-Editor for the preliminary enquiery.

References

Brock and Huang 2017; DOI: 10.1158/0008-5472.CAN-17-0448
Weinberg 2014; DOI:10.1016/j/cell.2014.03.004
Bizzarri et al., 2020; DOI:10.3390/e22080885
Amirouchene-Angelozzi et al., 2017; DOI: 10.1158/2159-8290.CD-17-0343
Trigos et al., 2018; 10.1038/bjc.2017.398
Pienta et al., 2020; DOI: 10.1158/1541-7786.MCR-19-1158
Erenpreisa et al., 2020; DOI: 10.1016/j.semcancer.2020.12.009
Ye et al., 2021; DOI: 10.3389/fcell.2021.676344
Erenpreisa and Cragg 2007; DOI: 10.1016/j.cellbi.2007.08.013
Bruggeman et al., 2018; DOI: 10.1038/s41388-018-0357-2

Dr. Jekaterina Erenpreisa
Prof. Dr. Mark Steven Cragg
Prof. Dr. Alessandro Giuliani
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

Cancer resistance
Cancer complexity
Cancer genome instability
Cancer Polyploidy and Aneuploidy
Cancer genome networks
Cancer cell life-cycle
Cancer genome chaos
Meiosis-related processes in cancer
The role of transposons in cancer
Epigenetic regulations of cancer
Phylogeny of cancer

Published Papers (11 papers)

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Editorial

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6 pages, 619 KiB

Open AccessEditorial

Special Issue “Advances in Genome Regulation in Cancer”

by Jekaterina Erenpreisa, Alessandro Giuliani and Mark Steven Cragg

Int. J. Mol. Sci. 2023, 24(19), 14567; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241914567 - 26 Sep 2023

Viewed by 644

Abstract

Cancer is globally increasing [...] Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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Research

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24 pages, 10870 KiB

Open AccessArticle

The Role of Mitotic Slippage in Creating a “Female Pregnancy-like System” in a Single Polyploid Giant Cancer Cell

by Kristine Salmina, Ninel Miriam Vainshelbaum, Madara Kreishmane, Inna Inashkina, Mark Steven Cragg, Dace Pjanova and Jekaterina Erenpreisa

Int. J. Mol. Sci. 2023, 24(4), 3237; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043237 - 06 Feb 2023

Cited by 4 | Viewed by 1738

Abstract

In our recent work, we observed that triple-negative breast cancer MDA-MB-231 cells respond to doxorubicin (DOX) via “mitotic slippage” (MS), discarding cytosolic damaged DNA during the process that provides their resistance to this genotoxic treatment. We also noted two populations of polyploid giant cells: those budding surviving offspring, versus those reaching huge ploidy by repeated MS and persisting for several weeks. Their separate roles in the recovery from treatment remained unclear. The current study was devoted to characterising the origin and relationship of these two sub-populations in the context of MS. MS was hallmarked by the emergence of nuclear YAP1/OCT4A/MOS/EMI2-positivity featuring a soma-germ transition to the meiotic-metaphase-arrested “maternal germ cell”. In silico, the link between modules identified in the inflammatory innate immune response to cytosolic DNA and the reproductive module of female pregnancy (upregulating placenta developmental genes) was observed in polyploid giant cells. Asymmetry of the two subnuclei types, one repairing DNA and releasing buds enriched by CDC42/ACTIN/TUBULIN and the other persisting and degrading DNA in a polyploid giant cell, was revealed. We propose that when arrested in MS, a “maternal cancer germ cell” may be parthenogenetically stimulated by the placental proto-oncogene parathyroid-hormone-like-hormone, increasing calcium, thus creating a ”female pregnancy-like” system within a single polyploid giant cancer cell. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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26 pages, 7868 KiB

Open AccessArticle

The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction

by Ninel M. Vainshelbaum, Alessandro Giuliani, Kristine Salmina, Dace Pjanova and Jekaterina Erenpreisa

Int. J. Mol. Sci. 2022, 23(23), 14930; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314930 - 29 Nov 2022

Cited by 7 | Viewed by 1685

Abstract

The expression of gametogenesis-related (GG) genes and proteins, as well as whole genome duplications (WGD), are the hallmarks of cancer related to poor prognosis. Currently, it is not clear if these hallmarks are random processes associated only with genome instability or are programmatically linked. Our goal was to elucidate this via a thorough bioinformatics analysis of 1474 GG genes in the context of WGD. We examined their association in protein–protein interaction and coexpression networks, and their phylostratigraphic profiles from publicly available patient tumour data. The results show that GG genes are upregulated in most WGD-enriched somatic cancers at the transcriptome level and reveal robust GG gene expression at the protein level, as well as the ability to associate into correlation networks and enrich the reproductive modules. GG gene phylostratigraphy displayed in WGD+ cancers an attractor of early eukaryotic origin for DNA recombination and meiosis, and one relative to oocyte maturation and embryogenesis from early multicellular organisms. The upregulation of cancer–testis genes emerging with mammalian placentation was also associated with WGD. In general, the results suggest the role of polyploidy for soma–germ transition accessing latent cancer attractors in the human genome network, which appear as pre-formed along the whole Evolution of Life. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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22 pages, 4061 KiB

Open AccessArticle

Analysis of Dormancy-Associated Transcriptional Networks Reveals a Shared Quiescence Signature in Lung and Colorectal Cancer

by Adriano Cuccu, Federica Francescangeli, Maria Laura De Angelis, Alessandro Bruselles, Alessandro Giuliani and Ann Zeuner

Int. J. Mol. Sci. 2022, 23(17), 9869; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179869 - 30 Aug 2022

Cited by 9 | Viewed by 2343

Abstract

Quiescent cancer cells (QCCs) are a common feature of solid tumors, representing a major obstacle to the long-term success of cancer therapies. We isolated QCCs ex vivo from non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) xenografts with a label-retaining strategy and compared QCCs gene expression profiles to identify a shared “quiescence signature”. Principal Component Analysis (PCA) revealed a specific component neatly discriminating quiescent and replicative phenotypes in NSCLC and CRC. The discriminating component showed significant overlapping, with 688 genes in common including ZEB2, a master regulator of stem cell plasticity and epithelial-to-mesenchymal transition (EMT). Gene set enrichment analysis showed that QCCs of both NSCLC and CRC had an increased expression of factors related to stemness/self renewal, EMT, TGF-β, morphogenesis, cell adhesion and chemotaxis, whereas proliferating cells overexpressed Myc targets and factors involved in RNA metabolism. Eventually, we analyzed in depth by means of a complex network approach, both the ‘morphogenesis module’ and the subset of differentially expressed genes shared by NCSLC and CRC. This allowed us to recognize different gene regulation network wiring for quiescent and proliferating cells and to underpin few genes central for network integration that may represent new therapeutic vulnerabilities. Altogether, our results highlight common regulatory pathways in QCCs of lung and colorectal tumors that may be the target of future therapeutic interventions. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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10 pages, 1542 KiB

Open AccessArticle

Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer

by Marco Archetti

Int. J. Mol. Sci. 2022, 23(15), 8528; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158528 - 01 Aug 2022

Cited by 4 | Viewed by 1921

Abstract

Polyploidy is common in cancer cells and has implications for tumor progression and resistance to therapies, but it is unclear whether it is an adaptation of the tumor or the non-adaptive effect of genomic instability. I discuss the possibility that polyploidy reduces the deleterious effects of loss of heterozygosity, which arises as a consequence of mitotic recombination, and which in diploid cells leads instead to the rapid loss of complementation of recessive deleterious mutations. I use computational predictions of loss of heterozygosity to show that a population of diploid cells dividing by mitosis with recombination can be easily invaded by mutant polyploid cells or cells that divide by endomitosis, which reduces loss of complementation, or by mutant cells that occasionally fuse, which restores heterozygosity. A similar selective advantage of polyploidy has been shown for the evolution of different types of asexual reproduction in nature. This provides an adaptive explanation for cyclical ploidy, mitotic slippage and cell fusion in cancer cells. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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16 pages, 2229 KiB

Open AccessArticle

Therapy-Induced Senescent/Polyploid Cancer Cells Undergo Atypical Divisions Associated with Altered Expression of Meiosis, Spermatogenesis and EMT Genes

by Joanna Czarnecka-Herok, Malgorzata Alicja Sliwinska, Marcin Herok, Alicja Targonska, Anna Strzeszewska-Potyrala, Agnieszka Bojko, Artur Wolny, Grazyna Mosieniak and Ewa Sikora

Int. J. Mol. Sci. 2022, 23(15), 8288; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158288 - 27 Jul 2022

Cited by 10 | Viewed by 2769

Abstract

Upon anticancer treatment, cancer cells can undergo cellular senescence, i.e., the temporal arrest of cell division, accompanied by polyploidization and subsequent amitotic divisions, giving rise to mitotically dividing progeny. In this study, we sought to further characterize the cells undergoing senescence/polyploidization and their propensity for atypical divisions. We used p53-wild type MCF-7 cells treated with irinotecan (IRI), which we have previously shown undergo senescence/polyploidization. The propensity of cells to divide was measured by a BrdU incorporation assay, Ki67 protein level (cell cycle marker) and a time-lapse technique. Advanced electron microscopy-based cell visualization and bioinformatics for gene transcription analysis were also used. We found that after IRI-treatment of MCF-7 cells, the DNA replication and Ki67 level decreased temporally. Eventually, polyploid cells divided by budding. With the use of transmission electron microscopy, we showed the presence of mononuclear small cells inside senescent/polyploid ones. A comparison of the transcriptome of senescent cells at day three with day eight (when cells just start to escape senescence) revealed an altered expression of gene sets related to meiotic cell cycles, spermatogenesis and epithelial–mesenchymal transition. Although chemotherapy (DNA damage)-induced senescence is indispensable for temporary proliferation arrest of cancer cells, this response can be followed by their polyploidization and reprogramming, leading to more fit offspring. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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15 pages, 3310 KiB

Open AccessArticle

Necroptosis as a Novel Facet of Mitotic Catastrophe

by Aleksandra Yu. Egorshina, Alexey V. Zamaraev, Vitaliy O. Kaminskyy, Tatiana V. Radygina, Boris Zhivotovsky and Gelina S. Kopeina

Int. J. Mol. Sci. 2022, 23(7), 3733; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073733 - 29 Mar 2022

Cited by 5 | Viewed by 2928

Abstract

Mitotic catastrophe is a defensive mechanism that promotes elimination of cells with aberrant mitosis by triggering the cell-death pathways and/or cellular senescence. Nowadays, it is known that apoptosis, autophagic cell death, and necrosis could be consequences of mitotic catastrophe. Here, we demonstrate the ability of a DNA-damaging agent, doxorubicin, at 600 nM concentration to stimulate mitotic catastrophe. We observe that the inhibition of caspase activity leads to accumulation of cells with mitotic catastrophe hallmarks in which RIP1-dependent necroptotic cell death is triggered. The suppression of autophagy by a chemical inhibitor or ATG13 knockout upregulates RIP1 phosphorylation and promotes necroptotic cell death. Thus, in certain conditions mitotic catastrophe, in addition to apoptosis and autophagy, can precede necroptosis. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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Review

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16 pages, 1249 KiB

Open AccessReview

An Epigenetic LINE-1-Based Mechanism in Cancer

by Patrizia Lavia, Ilaria Sciamanna and Corrado Spadafora

Int. J. Mol. Sci. 2022, 23(23), 14610; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314610 - 23 Nov 2022

Cited by 8 | Viewed by 2285

Abstract

In the last fifty years, large efforts have been deployed in basic research, clinical oncology, and clinical trials, yielding an enormous amount of information regarding the molecular mechanisms of cancer and the design of effective therapies. The knowledge that has accumulated underpins the complexity, multifactoriality, and heterogeneity of cancer, disclosing novel landscapes in cancer biology with a key role of genome plasticity. Here, we propose that cancer onset and progression are determined by a stress-responsive epigenetic mechanism, resulting from the convergence of upregulation of LINE-1 (long interspersed nuclear element 1), the largest family of human retrotransposons, genome damage, nuclear lamina fragmentation, chromatin remodeling, genome reprogramming, and autophagy activation. The upregulated expression of LINE-1 retrotransposons and their protein products plays a key role in these processes, yielding an increased plasticity of the nuclear architecture with the ensuing reprogramming of global gene expression, including the reactivation of embryonic transcription profiles. Cancer phenotypes would thus emerge as a consequence of the unscheduled reactivation of embryonic gene expression patterns in an inappropriate context, triggering de-differentiation and aberrant proliferation in differentiated cells. Depending on the intensity of the stressing stimuli and the level of LINE-1 response, diverse degrees of malignity would be generated. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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22 pages, 2658 KiB

Open AccessReview

Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring

by Olga V. Anatskaya and Alexander E. Vinogradov

Int. J. Mol. Sci. 2022, 23(17), 9691; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179691 - 26 Aug 2022

Cited by 14 | Viewed by 3167

Abstract

Polyploid cells demonstrate biological plasticity and stress adaptation in evolution; development; and pathologies, including cardiovascular diseases, neurodegeneration, and cancer. The nature of ploidy-related advantages is still not completely understood. Here, we summarize the literature on molecular mechanisms underlying ploidy-related adaptive features. Polyploidy can regulate gene expression via chromatin opening, reawakening ancient evolutionary programs of embryonality. Chromatin opening switches on genes with bivalent chromatin domains that promote adaptation via rapid induction in response to signals of stress or morphogenesis. Therefore, stress-associated polyploidy can activate Myc proto-oncogenes, which further promote chromatin opening. Moreover, Myc proto-oncogenes can trigger polyploidization de novo and accelerate genome accumulation in already polyploid cells. As a result of these cooperative effects, polyploidy can increase the ability of cells to search for adaptive states of cellular programs through gene regulatory network rewiring. This ability is manifested in epigenetic plasticity associated with traits of stemness, unicellularity, flexible energy metabolism, and a complex system of DNA damage protection, combining primitive error-prone unicellular repair pathways, advanced error-free multicellular repair pathways, and DNA damage-buffering ability. These three features can be considered important components of the increased adaptability of polyploid cells. The evidence presented here contribute to the understanding of the nature of stress resistance associated with ploidy and may be useful in the development of new methods for the prevention and treatment of cardiovascular and oncological diseases. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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26 pages, 2121 KiB

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Interplay between Cell Death and Cell Proliferation Reveals New Strategies for Cancer Therapy

by Luke V. Loftus, Sarah R. Amend and Kenneth J. Pienta

Int. J. Mol. Sci. 2022, 23(9), 4723; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094723 - 25 Apr 2022

Cited by 30 | Viewed by 4277

Abstract

Cell division and cell death are fundamental processes governing growth and development across the tree of life. This relationship represents an evolutionary link between cell cycle and cell death programs that is present in all cells. Cancer is characterized by aberrant regulation of both, leading to unchecked proliferation and replicative immortality. Conventional anti-cancer therapeutic strategies take advantage of the proliferative dependency of cancer yet, in doing so, are triggering apoptosis, a death pathway to which cancer is inherently resistant. A thorough understanding of how therapeutics kill cancer cells is needed to develop novel, more durable treatment strategies. While cancer evolves cell-intrinsic resistance to physiological cell death pathways, there are opportunities for cell cycle agnostic forms of cell death, for example, necroptosis or ferroptosis. Furthermore, cell cycle independent death programs are immunogenic, potentially licensing host immunity for additional antitumor activity. Identifying cell cycle independent vulnerabilities of cancer is critical for developing alternative strategies that can overcome therapeutic resistance. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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18 pages, 2992 KiB

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Life Entrapped in a Network of Atavistic Attractors: How to Find a Rescue

by Andrzej Kasperski

Int. J. Mol. Sci. 2022, 23(7), 4017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23074017 - 05 Apr 2022

Cited by 9 | Viewed by 5034

Abstract

In view of unified cell bioenergetics, cell bioenergetic problems related to cell overenergization can cause excessive disturbances in current cell fate and, as a result, lead to a change of cell-fate. At the onset of the problem, cell overenergization of multicellular organisms (especially overenergization of mitochondria) is solved inter alia by activation and then stimulation of the reversible Crabtree effect by cells. Unfortunately, this apparently good solution can also lead to a much bigger problem when, despite the activation of the Crabtree effect, cell overenergization persists for a long time. In such a case, cancer transformation, along with the Warburg effect, may occur to further reduce or stop the charging of mitochondria by high-energy molecules. Understanding the phenomena of cancer transformation and cancer development has become a real challenge for humanity. To date, many models have been developed to understand cancer-related mechanisms. Nowadays, combining all these models into one coherent universal model of cancer transformation and development can be considered a new challenge. In this light, the aim of this article is to present such a potentially universal model supported by a proposed new model of cellular functionality evolution. The methods of fighting cancer resulting from unified cell bioenergetics and the two presented models are also considered. Full article

(This article belongs to the Special Issue Advances in Genome Regulation in Cancer)

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