bims-ovdlit 2023-05-14 papers

Issue of 2023‒05‒14
two papers selected by
Lara Paracchini
Humanitas Research

Elife. 2023 May 11. pii: e83867. [Epub ahead of print]12

High-grade serous ovarian carcinoma organoids as models of chromosomal instability.

Maria Vias, Lena Morrill Gavarró, Carolin M Sauer, Deborah A Sanders, Anna M Piskorz, Dominique-Laurent Couturier, Stéphane Ballereau, Bárbara Hernando, Michael P Schneider, James Hall, Filipe Correia-Martins, Florian Markowetz, Geoff Macintyre, James D Brenton.

High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ubiquitous TP53 mutation, profound chromosomal instability, and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs) and characterized them using bulk transcriptomic, bulk genomic, single-cell genomic, and drug sensitivity assays. We show that HGSOC PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype, and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide validated genomic models for studies of specific mutational processes and precision therapeutics.

Keywords: cancer biology; chromosomal instability; genetics; genomics; high-grade serous ovarian cancer; human; organoids

DOI: https://doi.org/10.7554/eLife.83867

Nat Rev Genet. 2023 May 11.

The epithelial-mesenchymal plasticity landscape: principles of design and mechanisms of regulation.

Jef Haerinck, Steven Goossens, Geert Berx.

Epithelial-mesenchymal plasticity (EMP) enables cells to interconvert between several states across the epithelial-mesenchymal landscape, thereby acquiring hybrid epithelial/mesenchymal phenotypic features. This plasticity is crucial for embryonic development and wound healing, but also underlies the acquisition of several malignant traits during cancer progression. Recent research using systems biology and single-cell profiling methods has provided novel insights into the main forces that shape EMP, which include the microenvironment, lineage specification and cell identity, and the genome. Additionally, key roles have emerged for hysteresis (cell memory) and cellular noise, which can drive stochastic transitions between cell states. Here, we review these forces and the distinct but interwoven layers of regulatory control that stabilize EMP states or facilitate epithelial-mesenchymal transitions (EMTs) and discuss the therapeutic potential of manipulating the EMP landscape.

DOI: https://doi.org/10.1038/s41576-023-00601-0