Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma.

Background: More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time.

Combined Inhibition of EZH2 and FGFR is Synergistic in BAP1-deficient Malignant Mesothelioma.

Unlabelled: Malignant mesothelioma is a highly aggressive tumor with a survival of only 4-18 months after diagnosis. Treatment options for this disease are limited. Immune checkpoint blockade using ipilimumab and nivolumab has recently been approved as a frontline therapy, but this led to only a small improvement in overall patient survival.

Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.

More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway.

Self-management support by health care providers in prenatal Shared Medical Appointments (CenteringPregnancy©) and prenatal individual appointments.

Objective: This cross-sectional questionnaire study investigates if there a difference in the extent to which health care providers in prenatal Shared Medical Appointments (CenteringPregnancy©) and in prenatal individual appointments support self-management in patient education. It also investigates if there is a difference in the extent to which health care providers in CenteringPregnancy@ and in individual appointments pay attention to the factors of the Integrated Model for Behavioral Change (I-Change) in supporting self-management.

Methods: Dutch health care providers in prenatal care were invited to fill out a questionnaire.

Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer.

Background: The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype and a basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options are limited, highlighting the need for the development of novel targeted therapies for this tumor subtype.

Methods: Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient breast tumors and blocking EZH2 enzymatic activity could be a potent treatment strategy.

Assessing Dutch women's experiences of labour and birth: adaptations and psychometric evaluations of the measures Mothers on Autonomy in Decision Making Scale, Mothers on Respect Index, and Childbirth Experience Questionnaire 2.0.

Background: The Mothers Autonomy in Decision Making Scale (MADM) assesses women's autonomy and role in decision making. The Mothers on Respect Index (MORi) asseses women's experiences of respect when interacting with their healthcare providers. The Childbirth Experience Questionnaire 2.

Enhancer of Zeste Homolog 2 (EZH2) Contributes to Rod Photoreceptor Death Process in Several Forms of Retinal Degeneration and Its Activity Can Serve as a Biomarker for Therapy Efficacy.

Inherited retinal dystrophies (IRD) are due to various gene mutations. Each mutated gene instigates a specific cell homeostasis disruption, leading to a modification in gene expression and retinal degeneration. We previously demonstrated that the polycomb-repressive complex-1 (PRC1) markedly contributes to the cell death process.

USP15 Deubiquitinase Safeguards Hematopoiesis and Genome Integrity in Hematopoietic Stem Cells and Leukemia Cells.

Altering ubiquitination by disruption of deubiquitinating enzymes (DUBs) affects hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. Here, we systematically inactivate DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNA (shRNA) screens.

A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition.

BMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation.

Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice.

We have generated mouse models of malignant mesothelioma (MM) based upon disruption of the Bap1, Nf2, and Cdkn2ab tumor suppressor loci in various combinations as also frequently observed in human MM. Inactivation of all three loci in the mesothelial lining of the thoracic cavity leads to a highly aggressive MM that recapitulates the histological features and gene expression profile observed in human patients. The tumors also show a similar inflammatory phenotype.

Bmi1 restricts the adipogenic differentiation of bone marrow stromal cells to maintain the integrity of the hematopoietic stem cell niche.

The polycomb group protein Bmi1 maintains hematopoietic stem cell (HSC) functions. We previously reported that Bmi1-deficient mice exhibited progressive fatty changes in bone marrow (BM). A large portion of HSCs reside in the perivascular niche created partly by endothelial cells and leptin receptor (LepR) BM stromal cells.

EZH2 Is Overexpressed in -like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy.

Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature ("") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human -deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in -deficient murine mammary tumors.

Experimental Design: EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing.

Multiplexed Cas9 targeting reveals genomic location effects and gRNA-based staggered breaks influencing mutation efficiency.

Understanding the impact of guide RNA (gRNA) and genomic locus on CRISPR-Cas9 activity is crucial to design effective gene editing assays. However, it is challenging to profile Cas9 activity in the endogenous cellular environment. Here we leverage our TRIP technology to integrate ~ 1k barcoded reporter genes in the genomes of mouse embryonic stem cells.

Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities.

Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2.

A new transgenic mouse model for conditional overexpression of the Polycomb Group protein EZH2.

The Polycomb Group protein EZH2 is upregulated in most prostate cancers, and its overexpression is associated with poor prognosis. Most insights into the functional role of EZH2 in prostate cancer have been gained using cell lines and EZH2 inactivation studies. However, the question remains whether overexpression of EZH2 can initiate prostate tumourigenesis or drive tumour progression.

TRIM28 is an Epigenetic Barrier to Induced Pluripotent Stem Cell Reprogramming.

Since the discovery of induced pluripotent stem cells there has been intense interest in understanding the mechanisms that allow a somatic cell to be reprogrammed back to a pluripotent state. Several groups have studied the alterations in gene expression that occur as somatic cells modify their genome to that of an embryonic stem cell. Underpinning many of the gene expression changes are modifications to the epigenetic profile of the associated chromatin.

Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition.

EZH2 inhibitors have gained great interest for their use as anti-cancer therapeutics. However, most research has focused on EZH2 mutant cancers and recently adverse effects of EZH2 inactivation have come to light. To determine whether colorectal cancer cells respond to EZH2 inhibition and to explore which factors influence the degree of response, we treated a panel of 20 organoid lines derived from human colon tumors with different concentrations of the EZH2 inhibitor GSK126.

Deletion of Polycomb Repressive Complex 2 From Mouse Intestine Causes Loss of Stem Cells.

Background & Aims: The polycomb repressive complex 2 (PRC2) regulates differentiation by contributing to repression of gene expression and thereby stabilizing the fate of stem cells and their progeny. PRC2 helps to maintain adult stem cell populations, but little is known about its functions in intestinal stem cells. We studied phenotypes of mice with intestine-specific deletion of the PRC2 proteins embryonic ectoderm development (EED) (a subunit required for PRC2 function) and enhancer of zeste homolog 2 (EZH2) (a histone methyltransferase).

Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer.

Polycomb repressive complexes (PRC) are frequently implicated in human cancer, acting either as oncogenes or tumor suppressors. Here, we show that PRC2 is a critical regulator of KRAS-driven non-small cell lung cancer progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances KRAS-driven adenomagenesis and inflammation, respectively.

Applications of DNA integrating elements: Facing the bias bully.

Retroviruses and DNA transposons are an important part of molecular biologists' toolbox. The applications of these elements range from functional genomics to oncogene discovery and gene therapy. However, these elements do not integrate uniformly across the genome, which is an important limitation to their use.

Context-dependent actions of Polycomb repressors in cancer.

Polycomb Group (PcG) proteins form Polycomb Repressive Complexes (PRCs) that function as epigenetic repressors of gene expression. The large variety of PcG proteins, in addition to the high number of paralogs, allows for the formation of diverse PRCs with different properties, providing fine-tuned control over cell specification. Initially identified as being oncogenes, a small number of PcG genes are involved in tumor development in part through the repression of the CDKN2A locus.

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression.

EZH2 is frequently overexpressed in glioblastoma (GBM), suggesting an oncogenic function that could be a target for therapeutic intervention. However, reduced EZH2 activity can also promote tumorigenesis, leading to concerns about the use of EZH2 inhibitors. Here, we provide further insight about the effects of prolonged Ezh2 inhibition in glioblastoma using preclinical mouse models and primary tumor-derived human GBM cell lines.

Loss of PRDM11 promotes MYC-driven lymphomagenesis.

The PR-domain (PRDM) family of genes encodes transcriptional regulators, several of which are deregulated in cancer. By using a functional screening approach, we sought to identify novel tumor suppressors among the PRDMs. Here we demonstrate oncogenic collaboration between depletion of the previously uncharacterized PR-domain family member Prdm11 and overexpression of MYC.