Polo-like kinase 1 maintains transcription and chromosomal accessibility during mitosis.

Transcription persists at low levels in mitotic cells and plays essential roles in mitotic fidelity and chromosomal dynamics. However, the detailed regulatory network of mitotic transcription remains largely unresolved. Here, we report the novel role of Polo-like kinase 1 (Plk1) in maintaining mitotic transcription.

Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer.

Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making. Previous work has relied on poor models of the most common subtypes of epithelial ovarian cancers and necessitates a careful examination of the most suitable in vitro models. We performed extensive drug dose response assays and gene expression profiling on 36 ovarian cancer cell lines across over seven subtypes.

MYC Regulates a DNA Repair Gene Expression Program in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.

Background/objectives: SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the oncogene.

Loss of SMARCA4 Leads to Intron Retention and Generation of Tumor-Associated Antigens in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.

Unlabelled: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. In this study, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation.

Polo-like kinase 1 maintains transcription and chromosomal accessibility during mitosis.

Unlabelled: Transcription persists at low levels in mitotic cells and plays essential roles in mitotic fidelity and chromosomal dynamics. However, the detailed regulatory network of mitotic transcription remains largely unresolved. Here, we report the novel role of Polo-like kinase 1 (Plk1) in maintaining mitotic transcription.

Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type.

Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare ovarian cancer affecting young females and is driven by the loss of both SWI/SNF ATPases SMARCA4 and SMARCA2. As loss of SWI/SNF alters enhancers, we hypothesized that super-enhancers, which regulate oncogene expression in cancer, are disparately impacted by SWI/SNF loss. We discovered differences between SWI/SNF occupancy at enhancers vs.

Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer cell lines and isogenic models.

Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making as of yet. Two particular challenges faced in mechanistically deciphering platinum responsiveness in ovarian cancer have been the suitability of cell line models for ovarian cancer subtypes and the availability of information on comparatively how sensitive ovarian cancer cell lines are to platinum. We performed one of the most comprehensive profiles to date on 36 ovarian cancer cell lines across over seven subtypes and integrated drug response and multiomic data to improve on our understanding of the best cell line models for platinum responsiveness in ovarian cancer.

TP53 mutations and the association with platinum resistance in high grade serous ovarian carcinoma.

Objectives: Alterations in the tumor suppressor TP53 gene are the most common mutations in high grade serous ovarian carcinoma. The impact of TP53 mutations on clinical outcomes and platinum resistance is controversial. We sought to evaluate the genomic profile of high grade serous ovarian carcinoma and explore the association of TP53 mutations with platinum resistance.

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV replication in M3+ Mauritian cynomolgus macaques initiated on ART two weeks post-infection.

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). None of the MCMs possessed MHC haplotypes previously associated with SIV control.

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel.

Background: A subset of triple-negative breast cancers (TNBCs) have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. PIKTOR, a combination of TAK-228 (TORC1/2 inhibitor) and TAK-117 (PI3Kα inhibitor), is hypothesized to increase genomic instability and increase DNA damage repair (DDR) deficiency, leading to increased sensitivity to DNA-damaging chemotherapy and to immune checkpoint blockade inhibitors.

Methods: 10 metastatic TNBC patients received 4 mg TAK-228 and 200 mg TAK-117 (PIKTOR) orally each day for 3 days followed by 4 days off, weekly, until disease progression (PD), followed by intravenous cisplatin 75 mg/m plus nab paclitaxel 220 mg/m every 3 weeks for up to 6 cycles.

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV in Mauritian cynomolgus macaques.

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). For six months after ART withdrawal, we observed undetectable or transient viremia in seven of eight MCMs.

The COX-2-PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas.

Unlabelled: The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2-derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4-PI3K-Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4-PI3K-Akt-NFκB-PD-1 signaling pathway.

Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer.

Background: Upregulated glucose metabolism is a common feature of tumors. Glucose can be broken down by either glycolysis or the oxidative pentose phosphate pathway (oxPPP). The relative usage within tumors of these catabolic pathways remains unclear.

Improved methods for RNAseq-based alternative splicing analysis.

The robust detection of disease-associated splice events from RNAseq data is challenging due to the potential confounding effect of gene expression levels and the often limited number of patients with relevant RNAseq data. Here we present a novel statistical approach to splicing outlier detection and differential splicing analysis. Our approach tests for differences in the percentages of sequence reads representing local splice events.

Re-expression of SMARCA4/BRG1 in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in SCCOHT cell lines +/- BRG1 reexpression.

Small-Cell Carcinoma of the Ovary, Hypercalcemic Type-Genetics, New Treatment Targets, and Current Management Guidelines.

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in , which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit.

Prostaglandin E Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.

Background & Aims: Prostaglandin E (PGE) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE on colorectal cancer (CRC) development.

Methods: We incubated LS174T colorectal cancer cells with PGE or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs.

Histone Deacetylase Inhibitors Synergize with Catalytic Inhibitors of EZH2 to Exhibit Antitumor Activity in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival.

Identification of Driver Mutations in Rare Cancers: The Role of SMARCA4 in Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT).

Cancer is a complex genetic disease that can arise through the stepwise accumulation of mutations in oncogenes and tumor suppressor genes in a variety of different tissues. While the varied landscapes of mutations driving common cancer types such as lung, breast, and colorectal cancer have been comprehensively charted, the genetic underpinnings of many rare cancers remain poorly defined. Study of rare cancers faces unique methodological challenges, but collaborative enterprises that incorporate next generation sequencing, reach across disciplines (i.

The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.

Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodelling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodelling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation.

Streamlining gene expression analysis: integration of co-culture and mRNA purification.

Co-culture of multiple cell types within a single device enables the study of paracrine signaling events. However, extracting gene expression endpoints from co-culture experiments is laborious, due in part to pre-PCR processing of the sample (i.e.

Hormonally responsive breast cancer cells in a microfluidic co-culture model as a sensor of microenvironmental activity.

Breast cancer cell growth and therapeutic response are manipulated extrinsically by microenvironment signals. Despite recognition of the importance of the microenvironment in a variety of tumor processes, predictive measures that incorporate the activity of the surrounding cellular environment are lacking. In contrast, tumor cell biomarkers are well established in the clinic.