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

Vainshelbaum, Ninel M.; Giuliani, Alessandro; Salmiņa, Kristīne; Pjanova, Dace; Ērenpreisa, Jekaterina

doi:10.3390/ijms232314930

Cited by 10 publications

(28 citation statements)

References 142 publications

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“…Among the most strongly upregulated GO processes in polyploid vs. diploid cancer cells is the ‘female meiotic nuclear division’. This observation confirms previous reports on the activation of meiotic genes in polyploid cancer cells [ 95 , 96 , 97 , 98 ]. This fact can be a sign of genetic recombination, which is reminiscent of sexual generations arising in apomictic (clonal) animal and plant populations under stressful conditions and may be inherited from the evolutionary past.…”

Section: Discussionsupporting

confidence: 93%

Systemic Alterations of Cancer Cells and Their Boost by Polyploidization: Unicellular Attractor (UCA) Model

Vinogradov

Anatskaya

2023

IJMS

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Using meta-analyses, we introduce a unicellular attractor (UCA) model integrating essential features of the ‘atavistic reversal’, ‘cancer attractor’, ‘somatic mutation’, ‘genome chaos’, and ‘tissue organization field’ theories. The ‘atavistic reversal’ theory is taken as a keystone. We propose a possible mechanism of this reversal, its refinement called ‘gradual atavism’, and evidence for the ‘serial atavism’ model. We showed the gradual core-to-periphery evolutionary growth of the human interactome resulting in the higher protein interaction density and global interactome centrality in the UC center. In addition, we revealed that UC genes are more actively expressed even in normal cells. The modeling of random walk along protein interaction trajectories demonstrated that random alterations in cellular networks, caused by genetic and epigenetic changes, can result in a further gradual activation of the UC center. These changes can be induced and accelerated by cellular stress that additionally activates UC genes (especially during cell proliferation), because the genes involved in cellular stress response and cell cycle are mostly of UC origin. The functional enrichment analysis showed that cancer cells demonstrate the hyperactivation of energetics and the suppression of multicellular genes involved in communication with the extracellular environment (especially immune surveillance). Collectively, these events can unleash selfish cell behavior aimed at survival at all means. All these changes are boosted by polyploidization. The UCA model may facilitate an understanding of oncogenesis and promote the development of therapeutic strategies.

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Section: Discussionsupporting

confidence: 93%

Systemic Alterations of Cancer Cells and Their Boost by Polyploidization: Unicellular Attractor (UCA) Model

Vinogradov

Anatskaya

2023

IJMS

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“…Because of renewed interest in the atavistic theory of cancer [ 16 ], and an understanding of how cancer attractors during evolution are associated with polyploidy related to asexual reproduction, as recently identified in the TCGA database, including for breast carcinoma [ 17 ], we were interested in if and how these differences in gene expression changed the phylostratigraphic gene profiles.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore it is interesting that recently we revealed oocyte maturation and meiotic cell division in the STRING PPI network of the TCGA database BRCA (and some other cancers) patient sample cohort in association with whole genome duplications [ 17 ]. So, the current in silico and immunofluorescence data in our MDA-MB-231-DOX model confirm the reality of such cell-fate change of somatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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

Salmiņa

Vainshelbaum

Kreišmane

et al. 2023

IJMS

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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.

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“…Beyond the association between NLI and the well-established features of heart pathology in the main signaling pathways, our data also revealed the morphologic and transcriptomic traits of increased polyploidy that are also known to accompany various heart diseases, including tetralogy of Fallot, cardiomyopathy, hypertension, and ischemic heart disease [ 14 , 51 , 89 , 129 , 130 , 131 ]. Among these features are the response to DNA and telomere damage and the impairment of circadian entrainment [ 73 , 132 , 133 , 134 ]. Our data also uncovered ploidy-related manifestations of the fetal phenotype in the signaling pathways and metabolism [ 88 , 135 , 136 , 137 ].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

Anatskaya

Runov

Ponomartsev

et al. 2023

IJMS

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Many cardiovascular diseases originate from growth retardation, inflammation, and malnutrition during early postnatal development. The nature of this phenomenon is not completely understood. Here we aimed to verify the hypothesis that systemic inflammation triggered by neonatal lactose intolerance (NLI) may exert long-term pathologic effects on cardiac developmental programs and cardiomyocyte transcriptome regulation. Using the rat model of NLI triggered by lactase overloading with lactose and the methods of cytophotometry, image analysis, and mRNA-seq, we evaluated cardiomyocyte ploidy, signs of DNA damage, and NLI-associated long-term transcriptomic changes of genes and gene modules that differed qualitatively (i.e., were switched on or switched off) in the experiment vs. the control. Our data indicated that NLI triggers the long-term animal growth retardation, cardiomyocyte hyperpolyploidy, and extensive transcriptomic rearrangements. Many of these rearrangements are known as manifestations of heart pathologies, including DNA and telomere instability, inflammation, fibrosis, and reactivation of fetal gene program. Moreover, bioinformatic analysis identified possible causes of these pathologic traits, including the impaired signaling via thyroid hormone, calcium, and glutathione. We also found transcriptomic manifestations of increased cardiomyocyte polyploidy, such as the induction of gene modules related to open chromatin, e.g., “negative regulation of chromosome organization”, “transcription” and “ribosome biogenesis”. These findings suggest that ploidy-related epigenetic alterations acquired in the neonatal period permanently rewire gene regulatory networks and alter cardiomyocyte transcriptome. Here we provided first evidence indicating that NLI can be an important trigger of developmental programming of adult cardiovascular disease. The obtained results can help to develop preventive strategies for reducing the NLI-associated adverse effects of inflammation on the developing cardiovascular system.

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

Cited by 10 publications

References 142 publications

Systemic Alterations of Cancer Cells and Their Boost by Polyploidization: Unicellular Attractor (UCA) Model

Systemic Alterations of Cancer Cells and Their Boost by Polyploidization: Unicellular Attractor (UCA) Model

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

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

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