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Context-dependent effects of whole-genome duplication during mammary tumor recurrence.

ABSTRACT: Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.

SUBMITTER: Newcomb R

PROVIDER: S-EPMC8298634 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition.

Project description:Several lines of evidence indicate that whole-genome duplication resulting in tetraploidy facilitates carcinogenesis by providing an intermediate and metastable state more prone to generate oncogenic aneuploidy. Here, we report a novel strategy to preferentially kill tetraploid cells based on the abrogation of the spindle assembly checkpoint (SAC) via the targeting of TTK protein kinase (better known as monopolar spindle 1, MPS1). The pharmacological inhibition as well as the knockdown of MPS1 kills more efficiently tetraploid cells than their diploid counterparts. By using time-lapse videomicroscopy, we show that tetraploid cells do not survive the aborted mitosis due to SAC abrogation upon MPS1 depletion. On the contrary diploid cells are able to survive up to at least two more cell cycles upon the same treatment. This effect might reflect the enhanced difficulty of cells with whole-genome doubling to tolerate a further increase in ploidy and/or an elevated level of chromosome instability in the absence of SAC functions. We further show that MPS1-inhibited tetraploid cells promote mitotic catastrophe executed by the intrinsic pathway of apoptosis, as indicated by the loss of mitochondrial potential, the release of the pro-apoptotic cytochrome c from mitochondria, and the activation of caspases. Altogether, our results suggest that MPS1 inhibition could be used as a therapeutic strategy for targeting tetraploid cancer cells.

| S-EPMC4808040 | biostudies-literature

The house spider genome reveals an ancient whole-genome duplication during arachnid evolution.

Project description:BackgroundThe duplication of genes can occur through various mechanisms and is thought to make a major contribution to the evolutionary diversification of organisms. There is increasing evidence for a large-scale duplication of genes in some chelicerate lineages including two rounds of whole genome duplication (WGD) in horseshoe crabs. To investigate this further, we sequenced and analyzed the genome of the common house spider Parasteatoda tepidariorum.ResultsWe found pervasive duplication of both coding and non-coding genes in this spider, including two clusters of Hox genes. Analysis of synteny conservation across the P. tepidariorum genome suggests that there has been an ancient WGD in spiders. Comparison with the genomes of other chelicerates, including that of the newly sequenced bark scorpion Centruroides sculpturatus, suggests that this event occurred in the common ancestor of spiders and scorpions, and is probably independent of the WGDs in horseshoe crabs. Furthermore, characterization of the sequence and expression of the Hox paralogs in P. tepidariorum suggests that many have been subject to neo-functionalization and/or sub-functionalization since their duplication.ConclusionsOur results reveal that spiders and scorpions are likely the descendants of a polyploid ancestor that lived more than 450 MYA. Given the extensive morphological diversity and ecological adaptations found among these animals, rivaling those of vertebrates, our study of the ancient WGD event in Arachnopulmonata provides a new comparative platform to explore common and divergent evolutionary outcomes of polyploidization events across eukaryotes.

| S-EPMC5535294 | biostudies-literature

Ceramide kinase promotes tumor cell survival and mammary tumor recurrence.

Project description:Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTC) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that ceramide kinase (Cerk) is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously upregulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. We find that Cerk is rapidly upregulated in tumor cells following HER2/neu downregulation or treatment with Adriamycin and that Cerk is required for tumor cell survival following HER2/neu downregulation. Consistent with our observations in mouse models, analysis of gene expression profiles from more than 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with breast cancer. In addition, although CERK expression is associated with aggressive subtypes of breast cancer, including those that are estrogen receptor-negative, HER2(+), basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathologic variables. Together, our findings identify a functional role for Cerk in breast cancer recurrence and suggest the clinical utility of agents targeted against this prosurvival pathway.

| S-EPMC4285436 | biostudies-literature

A synergism between adaptive effects and evolvability drives whole genome duplication to fixation.

Project description:Whole genome duplication has shaped eukaryotic evolutionary history and has been associated with drastic environmental change and species radiation. While the most common fate of WGD duplicates is a return to single copy, retained duplicates have been found enriched for highly interacting genes. This pattern has been explained by a neutral process of subfunctionalization and more recently, dosage balance selection. However, much about the relationship between environmental change, WGD and adaptation remains unknown. Here, we study the duplicate retention pattern postWGD, by letting virtual cells adapt to environmental changes. The virtual cells have structured genomes that encode a regulatory network and simple metabolism. Populations are under selection for homeostasis and evolve by point mutations, small indels and WGD. After populations had initially adapted fully to fluctuating resource conditions re-adaptation to a broad range of novel environments was studied by tracking mutations in the line of descent. WGD was established in a minority (?30%) of lineages, yet, these were significantly more successful at re-adaptation. Unexpectedly, WGD lineages conserved more seemingly redundant genes, yet had higher per gene mutation rates. While WGD duplicates of all functional classes were significantly over-retained compared to a model of neutral losses, duplicate retention was clearly biased towards highly connected TFs. Importantly, no subfunctionalization occurred in conserved pairs, strongly suggesting that dosage balance shaped retention. Meanwhile, singles diverged significantly. WGD, therefore, is a powerful mechanism to cope with environmental change, allowing conservation of a core machinery, while adapting the peripheral network to accommodate change.

| S-EPMC3990473 | biostudies-literature

Evolution after Whole-Genome Duplication: Teleost MicroRNAs.

Project description:MicroRNAs (miRNAs) are important gene expression regulators implicated in many biological processes, but we lack a global understanding of how miRNA genes evolve and contribute to developmental canalization and phenotypic diversification. Whole-genome duplication events likely provide a substrate for species divergence and phenotypic change by increasing gene numbers and relaxing evolutionary pressures. To understand the consequences of genome duplication on miRNA evolution, we studied miRNA genes following the teleost genome duplication (TGD). Analysis of miRNA genes in four teleosts and in spotted gar, whose lineage diverged before the TGD, revealed that miRNA genes were retained in ohnologous pairs more frequently than protein-coding genes, and that gene losses occurred rapidly after the TGD. Genomic context influenced retention rates, with clustered miRNA genes retained more often than nonclustered miRNA genes and intergenic miRNA genes retained more frequently than intragenic miRNA genes, which often shared the evolutionary fate of their protein-coding host. Expression analyses revealed both conserved and divergent expression patterns across species in line with miRNA functions in phenotypic canalization and diversification, respectively. Finally, major strands of miRNA genes experienced stronger purifying selection, especially in their seeds and 3'-complementary regions, compared with minor strands, which nonetheless also displayed evolutionary features compatible with constrained function. This study provides the first genome-wide, multispecies analysis of the mechanisms influencing metazoan miRNA evolution after whole-genome duplication.

| S-EPMC8321539 | biostudies-literature

Gene Duplication Analysis Reveals No Ancient Whole Genome Duplication but Extensive Small-Scale Duplications during Genome Evolution and Adaptation of <i>Schistosoma mansoni</i>.

Project description:Gene duplication (GD), thought to facilitate evolutionary innovation and adaptation, has been studied in many phylogenetic lineages. However, it remains poorly investigated in trematodes, a medically important parasite group that has been evolutionarily specialized during long-term host-parasite interaction. In this study, we conducted a genome-wide study of GD modes and contributions in Schistosoma mansoni, a pathogen causing human schistosomiasis. We combined several lines of evidence provided by duplicate age distributions, genomic sequence similarity, depth-of-coverage and gene synteny to identify the dominant drivers that contribute to the origins of new genes in this parasite. The gene divergences following duplication events (gene structure, expression and function retention) were also analyzed. Our results reveal that the genome lacks whole genome duplication (WGD) in a long evolutionary time and has few large segmental duplications, but is extensively shaped by the continuous small-scale gene duplications (SSGDs) (i.e., dispersed, tandem and proximal GDs) that may be derived from (retro-) transposition and unequal crossing over. Additionally, our study shows that the genes generated by tandem duplications have the smallest divergence during the evolution. Finally, we demonstrate that SSGDs, especially the tandem duplications, greatly contribute to the expansions of some preferentially retained pathogenesis-associated gene families that are associated with the parasite's survival during infection. This study is the first to systematically summarize the landscape of GDs in trematodes and provides new insights of adaptations to parasitism linked to GD events for these parasites.

| S-EPMC5613093 | biostudies-literature

Interspecific introgression mediates adaptation to whole genome duplication.

Project description:Adaptive gene flow is a consequential phenomenon across all kingdoms. Although recognition is increasing, there is no study showing that bidirectional gene flow mediates adaptation at loci that manage core processes. We previously discovered concerted molecular changes among interacting members of the meiotic machinery controlling crossover number upon adaptation to whole-genome duplication (WGD) in Arabidopsis arenosa. Here we conduct a population genomic study to test the hypothesis that adaptation to WGD has been mediated by adaptive gene flow between A. arenosa and A. lyrata. We find that A. lyrata underwent WGD more recently than A. arenosa, suggesting that pre-adapted alleles have rescued nascent A. lyrata, but we also detect gene flow in the opposite direction at functionally interacting loci under the most extreme levels of selection. These data indicate that bidirectional gene flow allowed for survival after WGD, and that the merger of these species is greater than the sum of their parts.

| S-EPMC6861236 | biostudies-literature

ADARp150 prohibits whole genome duplication

Project description:ADARp150 prohibits whole genome duplication

| PRJNA1090949 | ENA

The effects of repeated whole genome duplication events on the evolution of cytokinin signaling pathway.

Project description:BackgroundIt is thought that after whole-genome duplications (WGDs), a large fraction of the duplicated gene copies is lost over time while few duplicates are retained. Which factors promote survival or death of a duplicate remains unclear and the underlying mechanisms are poorly understood. According to the model of gene dosage balance, genes encoding interacting proteins are predicted to be preferentially co-retained after WGDs. Among these are genes encoding proteins involved in complexes or in signal transduction.ResultsWe have investigated the way that repeated WGDs during land plant evolution have affected cytokinin signaling to study patterns of gene duplicability and co-retention in this important signal transduction pathway. Through the integration of phylogenetic analyses with comparisons of genome collinearity, we have found that signal input mediated by cytokinin receptors proved to be highly conserved over long evolutionary time-scales, with receptors showing predominantly gene loss after repeated WGDs. However, the downstream elements, e,g. response regulators, were mainly retained after WGDs and thereby formed gene families in most plant lineages.ConclusionsGene dosage balance between the interacting components indicated by co-retention after WGDs seems to play a minor role in the evolution of cytokinin signaling pathway. Overall, core genes of cytokinin signaling show a highly heterogeneous pattern of gene retention after WGD, reflecting complex relationships between the various factors that shape the long-term fate of a duplicated gene.

| S-EPMC5975490 | biostudies-literature

ADARp150 prohibits whole genome duplication

Project description:Impaired control of the G1/S checkpoint allows initiation of DNA replication under non-permissive conditions. Unscheduled S-phase entry is associated with DNA replication stress, demanding for other checkpoints or cellular pathways to maintain proliferation. Here, we uncovered a requirement for ADARp150 to sustain proliferation of G1/S-checkpoint-defective cells under growth-restricting conditions. Besides its well-established mRNA editing function in inversely oriented short interspersed nuclear elements (SINEs), we found ADARp150 to exert a critical function in mitosis. ADARp150 depletion resulted in tetraploidization, impeding cell proliferation in mitogen-deprived conditions. Mechanistically we show that ADAR1 depletion induced aberrant expression of Cyclin B3, which was causative for mitotic failure and whole-genome duplication. Finally, we find that also in vivo ADAR1-depletion-provoked tetraploidization hampers tumor outgrowth.

2024-10-10 | GSE262277 | GEO

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