Dissecting the Origin of Heterogeneity in Uterine and Ovarian Carcinosarcomas.

Gynecologic carcinosarcomas (CS) are biphasic neoplasms composed of carcinomatous (C) and sarcomatous (S) malignant components. Because of their rarity and histologic complexity, genetic and functional studies on CS are scarce and the mechanisms of initiation and development remain largely unknown. Whole-genome analysis of the C and S components reveals shared genomic alterations, thus emphasizing the clonal evolution of CS. Reconstructions of the evolutionary history of each tumor further reveal that C and S samples are composed of both ancestral cell populations and component-specific subclones, supporting a common origin followed by distinct evolutionary trajectories. However, while we do not find any recurrent genomic features associated with phenotypic divergence, transcriptomic and methylome analyses identify a common mechanism across the cohort, the epithelial-to-mesenchymal transition (EMT), suggesting a role for nongenetic factors in inflicting changes to cellular fate. Altogether, these data accredit the hypothesis that CS tumors are driven by both clonal evolution and transcriptomic reprogramming, essential for susceptibility to transdifferentiation upon encountering environmental cues, thus linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences. Significance: We have provided a detailed characterization of the genomic landscape of CS and identified EMT as a common mechanism associated with phenotypic divergence, linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences.

Evolution of holocentric chromosomes: Drivers, diversity, and deterrents.

Centromeres are specialized chromosomal regions that recruit kinetochore proteins and mediate spindle microtubule attachment to ensure faithful chromosome segregation during mitosis and meiosis. Centromeres can be restricted to one region of the chromosome. Named "monocentromere", this type represents the most commonly found centromere organization across eukaryotes. Alternatively, centromeres can also be assembled at sites chromosome-wide. This second type is called "holocentromere". Despite their early description over 100 years ago, research on holocentromeres has lagged behind that of monocentromeres. Nevertheless, the application of next generation sequencing approaches and advanced microscopic technologies enabled recent advances understanding the molecular organization and regulation of holocentromeres in different organisms. Here we review the current state of research on holocentromeres focusing on evolutionary considerations. First, we provide a brief historical perspective on the discovery of holocentric chromosomes. We then discuss models/drivers that have been proposed over the years to explain the evolutionary transition from mono- to holocentric chromosomes. We continue to review the description of holocentric chromosomes in diverse eukaryotic groups and then focus our discussion on a specific and recently characterized type of holocentromere organization in insects that functions independently of the otherwise essential centromeric marker protein CenH3, thus providing novel insights into holocentromere evolution in insects. Finally, we propose reasons to explain why the holocentric trait is not more frequent across eukaryotes despite putative selective advantages.

Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis.

Senescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the proliferation of damaged cells. Cells undergoing senescence sustain important morphological changes, chromatin remodeling and metabolic reprogramming, and secrete pro-inflammatory factors termed senescence-associated secretory phenotype (SASP). SASP activation is required for the clearance of senescent cells by innate immunity. Therefore, escape from senescence and the associated immune editing would be a prerequisite for tumor initiation and progression as well as therapeutic resistance. One of the possible mechanisms for overcoming senescence could be the acquisition of cellular plasticity resulting from the accumulation of genomic alterations and genetic and epigenetic reprogramming. The modified composition of the SASP produced by these reprogrammed cancer cells would create a permissive environment, allowing their immune evasion. Additionally, the SASP produced by cancer cells could enhance the cellular plasticity of neighboring cells, thus hindering their recognition by the immune system. Here, we propose a comprehensive review of the literature, highlighting the role of cellular plasticity in the pro-tumoral activity of senescence in normal cells and in the cancer context.

Formation of the CenH3-Deficient Holocentromere in Lepidoptera Avoids Active Chromatin.

Despite the essentiality for faithful chromosome segregation, centromere architectures are diverse among eukaryotes1,2 and embody two main configurations: mono- and holocentromeres, referring, respectively, to localized or unrestricted distribution of centromeric activity. Of the two, some holocentromeres offer the curious condition of having arisen independently in multiple insects, most of which have lost the otherwise essential centromere-specifying factor CenH33 (first described as CENP-A in humans).4-7 The loss of CenH3 raises intuitive questions about how holocentromeres are organized and regulated in CenH3-lacking insects. Here, we report the first chromatin-level description of CenH3-deficient holocentromeres by leveraging recently identified centromere components6,7 and genomics approaches to map and characterize the holocentromeres of the silk moth Bombyx mori, a representative lepidopteran insect lacking CenH3. This uncovered a robust correlation between the distribution of centromere sites and regions of low chromatin activity along B. mori chromosomes. Transcriptional perturbation experiments recapitulated the exclusion of B. mori centromeres from active chromatin. Based on reciprocal centromere occupancy patterns observed along differentially expressed orthologous genes of Lepidoptera, we further found that holocentromere formation in a manner that is recessive to chromatin dynamics is evolutionarily conserved. Our results help us discuss the plasticity of centromeres in the context of a role for the chromosome-wide chromatin landscape in conferring centromere identity rather than the presence of CenH3. Given the co-occurrence of CenH3 loss and holocentricity in insects,7 we further propose that the evolutionary establishment of holocentromeres in insects was facilitated through the loss of a CenH3-specified centromere.

All that is old does not wither: Conservation of outer kinetochore proteins across all eukaryotes?

The kinetochore drives faithful chromosome segregation in all eukaryotes, yet the underlying machinery is diverse across species. D'Archivio and Wickstead (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201608043) apply sensitive homology predictions to identify proteins in kinetoplastids with similarity to canonical outer kinetochore proteins, suggesting some degree of universality in the eukaryotic kinetochore.