INHBA(+) cancer-associated fibroblasts generate an immunosuppressive tumor microenvironment in ovarian cancer.

Effective targeting of cancer-associated fibroblasts (CAFs) is hindered by the lack of specific biomarkers and a poor understanding of the mechanisms by which different populations of CAFs contribute to cancer progression. While the role of TGFβ in CAFs is well-studied, less attention has been focused on a structurally and functionally similar protein, Activin A (encoded by INHBA). Here, we identified INHBA(+) CAFs as key players in tumor promotion and immunosuppression.

Are Epithelial Ovarian Cancers of the Mesenchymal Subtype Actually Intraperitoneal Metastases to the Ovary?

Primary ovarian high-grade serous carcinoma (HGSC) has been classified into 4 molecular subtypes: Immunoreactive, Proliferative, Differentiated, and Mesenchymal (Mes), of which the Mes subtype (Mes-HGSC) is associated with the worst clinical outcomes. We propose that Mes-HGSC comprise clusters of cancer and associated stromal cells that detached from tumors in the upper abdomen/omentum and disseminated in the peritoneal cavity, including to the ovary. Using comparative analyses of multiple transcriptomic data sets, we provide the following evidence that the phenotype of Mes-HGSC matches the phenotype of tumors in the upper abdomen/omentum: (1) irrespective of the primary ovarian HGSC molecular subtype, matched upper abdominal/omental metastases were typically of the Mes subtype, (2) the Mes subtype was present at the ovarian site only in patients with concurrent upper abdominal/omental metastases and not in those with HGSC confined to the ovary, and (3) ovarian Mes-HGSC had an expression profile characteristic of stromal cells in the upper abdominal/omental metastases.

Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors.

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms.

Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy.

Background: Autism spectrum disorder is commonly co-diagnosed intellectual disability, language disorder, anxiety, and epilepsy, however, symptom management is difficult due to the complex genetic nature of ASD.

Methods: We present a next-generation sequencing-based case study with both de novo and inherited genetic variants and highlight the impact of structural variants on post-translational regulation of protein expression. Since management of symptoms has classically been through pharmaceutical therapies, a pharmacogenomics screen was also utilized to determine possible drug/gene interactions.

The future of myeloma precision medicine: integrating the compendium of known drug resistance mechanisms with emerging tumor profiling technologies.

Multiple myeloma (MM) is a hematologic malignancy that is considered mostly incurable in large part due to the inability of standard of care therapies to overcome refractory disease and inevitable drug-resistant relapse. The post-genomic era has been a productive period of discovery where modern sequencing methods have been applied to large MM patient cohorts to modernize our current perception of myeloma pathobiology and establish an appreciation for the vast heterogeneity that exists between and within MM patients. Numerous pre-clinical studies conducted in the last two decades have unveiled a compendium of mechanisms by which malignant plasma cells can escape standard therapies, many of which have potentially quantifiable biomarkers.

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes.

Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM.

Glucose deprivation elicits phenotypic plasticity via ZEB1-mediated expression of NNMT.

Glucose is considered the primary energy source for all cells, and some cancers are addicted to glucose. Here, we investigated the functional consequences of chronic glucose deprivation in serous ovarian cancer cells. We found that cells resistant to glucose starvation (glucose-restricted cells) demonstrated increased metabolic plasticity that was dependent on NNMT (Nicotinamide N-methyltransferase) expression.

A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets.

Although cancer-associated fibroblasts (CAFs) are viewed as a promising therapeutic target, the design of rational therapy has been hampered by two key obstacles. First, attempts to ablate CAFs have resulted in significant toxicity because currently used biomarkers cannot effectively distinguish activated CAFs from non-cancer associated fibroblasts and mesenchymal progenitor cells. Second, it is unclear whether CAFs in different organs have different molecular and functional properties that necessitate organ-specific therapeutic designs.

Cyclin E as a potential therapeutic target in high grade serous ovarian cancer.

Cyclin E1 (CCNE1) gene amplification occurs in approximately 20% of ovarian high grade serous carcinoma (HGSC) and is associated with chemotherapy resistance and, in some studies, overall poor prognosis. The role of cyclin E1 in inducing S phase entry relies upon its interactions with cyclin dependent kinases (CDK), specifically CDK2. Therapies to target cyclin E1-related functions have centered on CDK inhibitors and proteasome inhibitors.

Screening cell mechanotype by parallel microfiltration.

Cell mechanical phenotype or 'mechanotype' is emerging as a valuable label-free biomarker. For example, marked changes in the viscoelastic characteristics of cells occur during malignant transformation and cancer progression. Here we describe a simple and scalable technique to measure cell mechanotype: this parallel microfiltration assay enables multiple samples to be simultaneously measured by driving cell suspensions through porous membranes.

Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D.

Cyclin E1 and RTK/RAS signaling drive CDK inhibitor resistance via activation of E2F and ETS.

High-grade serous ovarian cancers (HGSOC) are genomically complex, heterogeneous cancers with a high mortality rate, due to acquired chemoresistance and lack of targeted therapy options. Cyclin-dependent kinase inhibitors (CDKi) target the retinoblastoma (RB) signaling network, and have been successfully incorporated into treatment regimens for breast and other cancers. Here, we have compared mechanisms of response and resistance to three CDKi that target either CDK4/6 or CDK2 and abrogate E2F target gene expression.

VEGFR3 inhibition chemosensitizes ovarian cancer stemlike cells through down-regulation of BRCA1 and BRCA2.

In ovarian cancer, loss of BRCA gene expression in tumors is associated with improved response to chemotherapy and increased survival. A means to pharmacologically downregulate BRCA gene expression could improve the outcomes of patients with BRCA wild-type tumors. We report that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in ovarian cancer cells is associated with decreased levels of both BRCA1 and BRCA2.

Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment.

Background: Bortezomib is a proteasome inhibitor with minimal clinical activity as a monotherapy in solid tumours, but its combination with other targeted therapies is being actively investigated as a way to increase its anticarcinogenic properties. Here, we evaluate the therapeutic potential of co-treatment with bortezomib and indole-3-carbinol (I3C), a natural compound found in cruciferous vegetables, in human ovarian cancer.

Methods: We examined the effects of I3C, bortezomib and cisplatin in several human ovarian cancer cell lines.

Fluvastatin and cisplatin demonstrate synergistic cytotoxicity in epithelial ovarian cancer cells.

Objective: Statin therapy has been associated with prolonged survival in patients with ovarian cancer. We hypothesized that statins have a cytotoxic effect and that the combination of fluvastatin and cisplatin inhibits cellular proliferation in epithelial ovarian cancer cells.

Methods: Fluvastatin and cisplatin were examined in CAOV3 and SKOV3 human ovarian cancer cell lines.

Liver X receptor agonist inhibits proliferation of ovarian carcinoma cells stimulated by oxidized low density lipoprotein.

Objectives: We previously observed an association between ovarian cancer outcome and statin use and hypothesized lipoproteins have direct effects on ovarian cancer proliferation. Here we investigate the direct effects of low density lipoprotein (LDL) and oxidized LDL (oxLDL) on proliferation and the inhibitory effects of fluvastatin and a liver X receptor (LXR) agonist.

Methods: The effects of LDL, oxLDL, the LXR agonist TO901317, fluvastatin and cisplatin on cellular proliferation were determined using MTT assays.

Drosophila E2F1 has context-specific pro- and antiapoptotic properties during development.

E2F transcription factors are generally believed to be positive regulators of apoptosis. In this study, we show that dE2F1 and dDP are important for the normal pattern of DNA damage-induced apoptosis in Drosophila wing discs. Unexpectedly, the role that E2F plays varies depending on the position of the cells within the disc.

Native E2F/RBF complexes contain Myb-interacting proteins and repress transcription of developmentally controlled E2F target genes.

The retinoblastoma tumor suppressor protein (pRb) regulates gene transcription by binding E2F transcription factors. pRb can recruit several repressor complexes to E2F bound promoters; however, native pRb repressor complexes have not been isolated. We have purified E2F/RBF repressor complexes from Drosophila embryo extracts and characterized their roles in E2F regulation.

p55, the Drosophila ortholog of RbAp46/RbAp48, is required for the repression of dE2F2/RBF-regulated genes.

Many proteins have been proposed to be involved in retinoblastoma protein (pRB)-mediated repression, but it is largely uncertain which cofactors are essential for pRB to repress endogenous E2F-regulated promoters. Here we have taken advantage of the stream-lined Drosophila dE2F/RBF pathway, which has only two E2Fs (dE2F1 and dE2F2), and two pRB family members (RBF1 and RBF2). With RNA interference (RNAi), we depleted potential corepressors and looked for the elevated expression of groups of E2F target genes that are known to be directly regulated by RBF1 and RBF2.

Distinct mechanisms of E2F regulation by Drosophila RBF1 and RBF2.

RBF1, a Drosophila pRB family homolog, is required for cell cycle arrest and the regulation of E2F-dependent transcription. Here, we describe the properties of RBF2, a second family member. RBF2 represses E2F transcription and is present at E2F-regulated promoters.