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Frontiers in Plant Science 2023
PubMed: 38146271
DOI: 10.3389/fpls.2023.1340455 -
Microbiology Spectrum Feb 2024Microsporidia are obligate intracellular eukaryotic parasites with an extremely broad host range. They have both economic and public health importance. Ploidy in...
Microsporidia are obligate intracellular eukaryotic parasites with an extremely broad host range. They have both economic and public health importance. Ploidy in microsporidia is variable, with a few species formally identified as diploid and one as polyploid. Given the increase in the number of studies sequencing microsporidian genomes, it is now possible to assess ploidy levels across all currently explored microsporidian diversity. We estimate ploidy for all microsporidian data sets available on the Sequence Read Archive using k-mer-based analyses, indicating that polyploidy is widespread in Microsporidia and that ploidy change is dynamic in the group. Using genome-wide heterozygosity estimates, we also show that polyploid microsporidian genomes are relatively homozygous, and we discuss the implications of these findings on the timing of polyploidization events and their origin.IMPORTANCEMicrosporidia are single-celled intracellular parasites, distantly related to fungi, that can infect a broad range of hosts, from humans all the way to protozoans. Exploiting the wealth of microsporidian genomic data available, we use k-mer-based analyses to assess ploidy status across the group. Understanding a genome's ploidy is crucial in order to assemble it effectively and may also be relevant for better understanding a parasite's behavior and life cycle. We show that tetraploidy is present in at least six species in Microsporidia and that these polyploidization events are likely to have occurred independently. We discuss why these findings may be paradoxical, given that Microsporidia, like other intracellular parasites, have extremely small, reduced genomes.
Topics: Humans; Microsporidia; Phylogeny; Evolution, Molecular; Genome, Fungal; Polyploidy
PubMed: 38214524
DOI: 10.1128/spectrum.03669-23 -
Current Biology : CB Sep 2023Facultative parthenogenesis enables sexually reproducing organisms to switch between sexual and asexual parthenogenetic reproduction. To gain insights into this...
Facultative parthenogenesis enables sexually reproducing organisms to switch between sexual and asexual parthenogenetic reproduction. To gain insights into this phenomenon, we sequenced the genomes of sexually reproducing and parthenogenetic strains of Drosophila mercatorum and identified differences in the gene expression in their eggs. We then tested whether manipulating the expression of candidate gene homologs identified in Drosophila mercatorum could lead to facultative parthenogenesis in the non-parthenogenetic species Drosophila melanogaster. This identified a polygenic system whereby increased expression of the mitotic protein kinase polo and decreased expression of a desaturase, Desat2, caused facultative parthenogenesis in the non-parthenogenetic species that was enhanced by increased expression of Myc. The genetically induced parthenogenetic Drosophila melanogaster eggs exhibit de novo centrosome formation, fusion of the meiotic products, and the onset of development to generate predominantly triploid offspring. Thus, we demonstrate a genetic basis for sporadic facultative parthenogenesis in an animal.
Topics: Animals; Drosophila; Drosophila melanogaster; Parthenogenesis; Centrosome
PubMed: 37516115
DOI: 10.1016/j.cub.2023.07.006 -
JCI Insight Sep 2023Patients with triple-negative breast cancer remain at risk for metastatic disease despite treatment. The acquisition of chemoresistance is a major cause of tumor relapse...
Patients with triple-negative breast cancer remain at risk for metastatic disease despite treatment. The acquisition of chemoresistance is a major cause of tumor relapse and death, but the mechanisms are far from understood. We have demonstrated that breast cancer cells (BCCs) can engulf mesenchymal stem/stromal cells (MSCs), leading to enhanced dissemination. Here, we show that clinical samples of primary invasive carcinoma and chemoresistant breast cancer metastasis contain a unique hybrid cancer cell population coexpressing pancytokeratin and the MSC marker fibroblast activation protein-α. We show that hybrid cells form in primary tumors and that they promote breast cancer metastasis and chemoresistance. Using single-cell microfluidics and in vivo models, we found that there are polyploid senescent cells within the hybrid cell population that contribute to metastatic dissemination. Our data reveal that Wnt Family Member 5A (WNT5A) plays a crucial role in supporting the chemoresistance properties of hybrid cells. Furthermore, we identified that WNT5A mediates hybrid cell formation through a phagocytosis-like mechanism that requires BCC-derived IL-6 and MSC-derived C-C Motif Chemokine Ligand 2. These findings reveal hybrid cell formation as a mechanism of chemoresistance and suggest that interrupting this mechanism may be a strategy in overcoming breast cancer drug resistance.
Topics: Humans; Drug Resistance, Neoplasm; Cell Line, Tumor; Neoplasm Recurrence, Local; Mesenchymal Stem Cells; Triple Negative Breast Neoplasms
PubMed: 37607007
DOI: 10.1172/jci.insight.164216 -
Genetics Aug 2023Polyploidy is an important generator of evolutionary novelty across diverse groups in the Tree of Life, including many crops. However, the impact of whole-genome...
Polyploidy is an important generator of evolutionary novelty across diverse groups in the Tree of Life, including many crops. However, the impact of whole-genome duplication depends on the mode of formation: doubling within a single lineage (autopolyploidy) versus doubling after hybridization between two different lineages (allopolyploidy). Researchers have historically treated these two scenarios as completely separate cases based on patterns of chromosome pairing, but these cases represent ideals on a continuum of chromosomal interactions among duplicated genomes. Understanding the history of polyploid species thus demands quantitative inferences of demographic history and rates of exchange between subgenomes. To meet this need, we developed diffusion models for genetic variation in polyploids with subgenomes that cannot be bioinformatically separated and with potentially variable inheritance patterns, implementing them in the dadi software. We validated our models using forward SLiM simulations and found that our inference approach is able to accurately infer evolutionary parameters (timing, bottleneck size) involved with the formation of auto- and allotetraploids, as well as exchange rates in segmental allotetraploids. We then applied our models to empirical data for allotetraploid shepherd's purse (Capsella bursa-pastoris), finding evidence for allelic exchange between the subgenomes. Taken together, our model provides a foundation for demographic modeling in polyploids using diffusion equations, which will help increase our understanding of the impact of demography and selection in polyploid lineages.
Topics: Polyploidy; Biological Evolution; Hybridization, Genetic; Capsella; Demography
PubMed: 37279657
DOI: 10.1093/genetics/iyad107 -
Molecular Cancer Sep 2023The Eyes Absent (EYA) family of proteins is an atypical group of four dual-functioning protein phosphatases (PP), which have been linked to many vital cellular processes...
The Eyes Absent (EYA) family of proteins is an atypical group of four dual-functioning protein phosphatases (PP), which have been linked to many vital cellular processes and organogenesis pathways. The four family members of this PP family possess transcriptional activation and phosphatase functions, with serine/threonine and tyrosine phosphatase domains. EYA4 has been associated with several human cancers, with tumor-suppressing and tumor-promoting roles. However, EYA4 is the least well-characterized member of this unique family of PP, with its biological functions and molecular mechanisms in cancer progression, particularly in breast cancer, still largely unknown. In the present study, we found that the over-expression of EYA4 in breast tissue leads to an aggressive and invasive breast cancer phenotype, while the inhibition of EYA4 reduced tumorigenic properties of breast cancer cells in vitro and in vivo. Cellular changes downstream of EYA4, including cell proliferation and migration, may explain the increased metastatic power of breast cancer cells over-expressing EYA4. Mechanistically, EYA4 prevents genome instability by inhibiting the accumulation of replication-associated DNA damage. Its depletion results in polyploidy as a consequence of endoreplication, a phenomenon that can occur in response to stress. The absence of EYA4 leads to spontaneous replication stress characterized by the activation of the ATR pathway, sensitivity to hydroxyurea, and accumulation of endogenous DNA damage as indicated by increased γH2AX levels. In addition, we show that EYA4, specifically its serine/threonine phosphatase domain, plays an important and so far, unexpected role in replication fork progression. This phosphatase activity is essential for breast cancer progression and metastasis. Taken together, our data indicate that EYA4 is a novel potential breast cancer oncogene that supports primary tumor growth and metastasis. Developing therapeutics aimed at the serine/threonine phosphatase activity of EYA4 represents a robust strategy for killing breast cancer cells, to limit metastasis and overcome chemotherapy resistance caused by endoreplication and genomic rearrangements.
Topics: Humans; Female; Breast Neoplasms; Trans-Activators; Cell Line, Tumor; Protein Tyrosine Phosphatases; Phosphoprotein Phosphatases; Serine
PubMed: 37777742
DOI: 10.1186/s12943-023-01861-4 -
Emerging Topics in Life Sciences Dec 2023Biocultural diversity is the ever-evolving and irreplaceable sum total of all living organisms inhabiting the Earth. It plays a significant role in sustainable...
Biocultural diversity is the ever-evolving and irreplaceable sum total of all living organisms inhabiting the Earth. It plays a significant role in sustainable productivity and ecosystem services that benefit humanity and is closely allied with human cultural diversity. Despite its essentiality, biodiversity is seriously threatened by the insatiable and inequitable human exploitation of the Earth's resources. One of the benefits of biodiversity is its utilization in crop improvement, including cropping improvement (agronomic cultivation practices) and genetic improvement (plant breeding). Crop improvement has tended to decrease agricultural biodiversity since the origins of agriculture, but awareness of this situation can reverse this negative trend. Cropping improvement can strive to use more diverse cultivars and a broader complement of crops on farms and in landscapes. It can also focus on underutilized crops, including legumes. Genetic improvement can access a broader range of biodiversity sources and, with the assistance of modern breeding tools like genomics, can facilitate the introduction of additional characteristics that improve yield, mitigate environmental stresses, and restore, at least partially, lost crop biodiversity. The current legal framework covering biodiversity includes national intellectual property and international treaty instruments, which have tended to limit access and innovation to biodiversity. A global system of access and benefit sharing, encompassing digital sequence information, would benefit humanity but remains an elusive goal. The Kunming-Montréal Global Biodiversity Framework sets forth an ambitious set of targets and goals to be accomplished by 2030 and 2050, respectively, to protect and restore biocultural diversity, including agrobiodiversity.
PubMed: 38084755
DOI: 10.1042/ETLS20230067 -
Clinical Cancer Research : An Official... Aug 2023Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver...
PURPOSE
Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy.
EXPERIMENTAL DESIGN
Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models.
RESULTS
AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor.
CONCLUSIONS
BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
Topics: Humans; Antineoplastic Agents; Apoptosis; Aurora Kinase B; Cell Line, Tumor; Lung Neoplasms; Proteomics; Proto-Oncogene Proteins c-bcl-2; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays
PubMed: 37289191
DOI: 10.1158/1078-0432.CCR-23-0375 -
Cell Reports Dec 2023The carcinogenesis and progression of hepatocellular carcinoma (HCC) are closely related to viral infection and intestinal bacteria. However, little is known about...
The carcinogenesis and progression of hepatocellular carcinoma (HCC) are closely related to viral infection and intestinal bacteria. However, little is known about bacteria within the HCC tumor microenvironment. Here, we showed that intratumoral Mycoplasma hyorhinis (M. hyorhinis) promoted the initiation and progression of HCC by enhancing nuclear ploidy. We quantified M. hyorhinis in clinical tissue specimens of HCC and observed that patients with high M. hyorhinis load had poor prognosis. We found that gastrointestinal M. hyorhinis can retrogradely infect the liver through the oral-duodenal-hepatopancreatic ampulla route. We further found that the increases in mononuclear polyploidy and cancer stemness resulted from mitochondrial fission caused by intracellular M. hyorhinis. Mechanistically, M. hyorhinis infection promoted the decay of mitochondrial fusion protein (MFN) 1 mRNA in an m6A-dependent manner. Our findings indicated that M. hyorhinis infection promoted pathological polyploidization and suggested that Mycoplasma clearance with antibiotics or regulating mitochondrial dynamics might have the potential for HCC therapy.
Topics: Humans; Mycoplasma; Carcinoma, Hepatocellular; Liver Neoplasms; Mycoplasma hyorhinis; Mycoplasma Infections; Tumor Microenvironment
PubMed: 38088929
DOI: 10.1016/j.celrep.2023.113563 -
Cells Aug 2023Salinity stress affects plant growth and development by causing osmotic stress and nutrient imbalances through excess Na, K, and Cl ion accumulations that induce toxic... (Review)
Review
Salinity stress affects plant growth and development by causing osmotic stress and nutrient imbalances through excess Na, K, and Cl ion accumulations that induce toxic effects during germination, seedling development, vegetative growth, flowering, and fruit set. However, the effects of salt stress on growth and development processes, especially in polyploidized leguminous plants, remain unexplored and scantly reported compared to their diploid counterparts. This paper discusses the physiological and molecular response of legumes towards salinity stress-based osmotic and ionic imbalances in plant cells. A multigenic response involving various compatible solutes, osmolytes, ROS, polyamines, and antioxidant activity, together with genes encoding proteins involved in the signal transduction, regulation, and response mechanisms to this stress, were identified and discussed. This discussion reaffirms polyploidization as the driving force in plant evolution and adaptation to environmental stress constraints such as drought, feverish temperatures, and, in particular, salt stress. As a result, thorough physiological and molecular elucidation of the role of gene duplication through induced autopolyploidization and possible mechanisms regulating salinity stress tolerance in grain legumes must be further studied.
Topics: Fabaceae; Mutagens; Salt Tolerance; Salt Stress; Crops, Agricultural
PubMed: 37626892
DOI: 10.3390/cells12162082