Publications by authors named "Ronny Drapkin"

High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC.

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Article Synopsis
  • The study investigates how cancer cells influence the fitness of surrounding tumor microenvironment (TME) cells through a mechanism involving a long non-coding RNA called Tu-Stroma, which alters the expression of Flower isoforms, impacting their growth advantage.
  • The expression of Flower Win isoforms in cancer cells enhances their dominance over TME cells that express Flower Lose isoforms, leading to reduced fitness in the TME.
  • Targeting Flower proteins with a humanized monoclonal antibody in mice has shown promising results, significantly reducing cancer growth and metastasis while improving survival rates and protecting organs from potential lesions.
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High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early detection biomarkers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure.

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High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histological subtype of ovarian cancer, and often presents with metastatic disease. The drivers of metastasis in HGSOC remain enigmatic. APOBEC3A (A3A), an enzyme that generates mutations across various cancers, has been proposed as a mediator of tumor heterogeneity and disease progression.

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DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR.

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Article Synopsis
  • High-Grade Serous Ovarian Cancer (HGSOC) develops from precursors in the fallopian tubes, yet the molecular changes during this progression are poorly understood.
  • Researchers used advanced imaging and spatial transcriptomics to analyze tissue samples from different stages of HGSOC, revealing critical immune modulating mechanisms and molecular alterations associated with the disease's progression.
  • Findings indicate a shift from immune surveillance to immune suppression in the tumor microenvironment, offering insights into potential biomarkers and therapeutic targets for early detection and intervention in HGSOC.
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  • - Ovarian cancer is a major health concern for women, mainly due to the lack of effective screening methods, prompting this study to explore new diagnostic approaches. - Researchers analyzed cell-free DNA and protein biomarkers in 591 women to develop a machine learning model that achieved over 99% specificity and variable sensitivity across cancer stages for detecting ovarian cancer. - The results suggest that combining cfDNA fragmentome analysis with protein biomarkers significantly improves the detection and differentiation of ovarian cancers from benign masses, paving the way for better noninvasive screening methods.
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High grade serous ovarian carcinoma (HGSOC) is the most common and aggressive ovarian malignancy. Accumulating evidence indicates that HGSOC may originate from human fallopian tube epithelial cells (FTECs), although the exact pathogen(s) and/or molecular mechanism underlying the malignant transformation of FTECs is unclear. Here we show that human papillomavirus (HPV), which could reach FTECs via retrograde menstruation or sperm-carrying, interacts with the yes-associated protein 1 (YAP1) to drive the malignant transformation of FTECs.

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The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear, thus providing critical barriers to the development of prevention or early detection strategies for this deadly disease. Increasing evidence demonstrates most HGSOC starts in the fallopian tube epithelium (FTE). Current models propose HGSOC initiates when FTE cells acquire increasing numbers of mutations allowing cells to evolve into serous tubal intraepithelial carcinoma (STIC) precursors and then to full blown cancer.

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BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from replication stress and genotoxicity, but the specific mechanism(s) by which this is achieved to prevent early oncogenesis remains unclear. Here, we provide evidence that BRCA2 acts as a critical suppressor of head-on transcription-replication conflicts (HO-TRCs). Using Okazaki-fragment sequencing (Ok-seq) and computational analysis, we identified origins (dormant origins) that are activated near the transcription termination sites (TTS) of highly expressed, long genes in response to replication stress.

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High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause.

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Purpose: Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression.

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Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of BRCA-mutated breast cancer (BC), including triple-negative BC (TNBC) and ovarian cancer (OvCa). A key challenge is to identify the factors associated with PARPi resistance; although, previous studies suggest that platinum-based agents and PARPi share similar resistance mechanisms.

Methods: Olaparib-resistant (OlaR) cell lines were analyzed using HTG EdgeSeq miRNA Whole Transcriptomic Analysis (WTA).

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Background: Single-cell gene expression profiling provides unique opportunities to understand tumor heterogeneity and the tumor microenvironment. Because of cost and feasibility, profiling bulk tumors remains the primary population-scale analytical strategy. Many algorithms can deconvolve these tumors using single-cell profiles to infer their composition.

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an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival.

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Article Synopsis
  • * The LINE-1 ORF1p protein is overexpressed in various cancers and has negligible expression in normal tissues, indicating its potential as a highly specific blood-based cancer biomarker.
  • * Advanced digital immunoassays can detect low levels of ORF1p in plasma, showing promise for early detection of ovarian cancer and monitoring treatment responses in gastroesophageal cancers, suggesting it could be a valuable tool for cancer diagnosis and prognosis.
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Epigenetic aberrations, including posttranslational modifications of core histones, are major contributors to cancer. Here, we define the status of histone H2B monoubiquitylation (H2Bub1) in clear cell ovarian carcinoma (CCOC), low-grade serous carcinoma, and endometrioid carcinomas. We report that clear cell carcinomas exhibited profound loss, with nearly all cases showing low or negative H2Bub1 expression.

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The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or normal tissues.

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Purpose: Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP inhibitors (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi (olaparib) and ATRi (ceralasertib) in patients with acquired PARPi-resistant HGSOC.

Patients And Methods: Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)-deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression.

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Article Synopsis
  • The study investigates the roles of four transcription factors (MECOM, PAX8, SOX17, and WT1) as potential master regulators in high-grade serous ovarian cancer (HGSC) and their relationship with the fallopian tube secretory epithelium (FTSEC).
  • Researchers used various epigenome and RNA-seq techniques to analyze how these factors interact and regulate gene expression in both cancer and normal models.
  • The findings suggest that these transcription factors are crucial for HGSC tumor growth and survival but show different effects on FTSEC cells, indicating potential avenues for targeted cancer therapies.
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ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells.

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Article Synopsis
  • * The Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is found to be overexpressed in various cancers but not in normal tissues, highlighting its potential as a specific cancer biomarker.
  • * Researchers have developed highly sensitive digital immunoassays to detect ORF1p in blood samples, showing promise for early detection of ovarian cancer and improved monitoring of gastric and esophageal cancers, positioning it as a valuable multi-cancer biomarker.
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Long interspersed element 1 (LINE-1) open reading frame 1 protein (ORF1p) expression is a common feature of many cancer types, including high-grade serous ovarian carcinoma (HGSOC). Here, we report that ORF1p is not only expressed but also released by ovarian cancer and primary tumor cells. Immuno-multiple reaction monitoring-mass spectrometry assays showed that released ORF1p is confidently detectable in conditioned media, ascites, and patients' plasma, implicating ORF1p as a potential biomarker.

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Most ovarian high-grade serous carcinomas (HGSC) arise from Serous Tubal Intraepithelial Carcinoma (STIC) lesions in the distal end of the fallopian tube (FT). Formation of STIC lesions from FT secretory cells leads to seeding of the ovarian surface, with rapid tumor dissemination to other abdominal structures thereafter. It remains unclear how nascent malignant cells leave the FT to colonize the ovary.

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