bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract AP12: FOXM1 INDUCES DNA REPLICATION STRESS AND PROMOTES GENOMIC INSTABILITY DOWNSTREAM OF CYCLIN E1 IN HIGH-GRADE SEROUS OVARIAN CANCER
Authors: Barger Carter J , Biswas Kajal , Chee Linda , Drapkin Ronny , Sharan Shyam , Karpf Adam R. 
Published: June 2021

Abstract
PURPOSE: Genomic instability (GI) is a hallmark of high-grade serous ovarian cancer (HGSC), and induction of the FOXM1 transcription factor regulatory network is the second most frequent genetic alteration in HGSC. FOXM1 expression is associated with cancer GI, but the mechanistic link is unknown. DNA replication stress (DRS), which involves altered replication fork dynamics, is a key contributor to cancer GI. FOXM1 and cyclin E1 (CCNE1) are both expressed in STIC lesions in the fallopian tube epithelium (FTE), and CCNE1-CDK2 enhances FOXM1 transcriptional activity. Based on these observations, we hypothesized that: 1) FOXM1 is linked to cancer GI through the induction of DRS, and 2) FOXM1 promotes GI downstream of CCNE1, by promoting unscheduled M phase entry in cells that have not completed DNA synthesis.
METHODS: We determined associations between FOXM1 and markers of DRS and GI in TCGA HGSC data. We overexpressed FOXM1c and a DNA binding domain mutant (DBD) in immortalized FTE cells and characterized the impact on DRS, DNA replication, and DNA damage. We determined the impact of CCNE1 on FOXM1 expression in immortalized FTE cells. We determined the combined effect of CCNE1 and FOXM1 on GI in FTE cells.
RESULTS: FOXM1 was significantly associated with markers of DRS (CHK1-Ser345) and GI (fractional copy number altered genome (CNA)) in TCGA HGSC data. FOXM1 expression, but not its DBD mutant, induced biomarkers of DRS and DNA damage in hTERT/mutant Tp53 immortalized FTE cells. Unexpectedly, FOXM1c increased DNA replication fork rate in FTE cells. Increased fork rate is a novel and recently recognized cause of DRS. CCNE1 expression in FTE cells induced and activated FOXM1, promoting mitotic entry. FOXM1 and CCNE1 co-expression in FTE cells induced an expression signature of GI, and TCGA HGSC tumors with FOXM1 and CCNE1 co-expression showed significantly increased GI.
CONCLUSIONS: We demonstrate that FOXM1 induces DRS and DNA damage in FTE cells, providing an explanation for the known link between FOXM1 and GI. Notably, FOXM1 induces a novel form of DRS involving increased replication fork rate. We show that CCNE1 activates FOXM1, which in turn promotes mitotic entry and GI. These data reveal a potentially major form of oncogenic collaboration in HGSC, and has implications for HGSC treatment approaches that promote DRS or inhibit the cellular DRS response.
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Citation Format: Carter J Barger, Kajal Biswas, Linda Chee, Ronny Drapkin, Shyam Sharan, Adam R. Karpf. FOXM1 INDUCES DNA REPLICATION STRESS AND PROMOTES GENOMIC INSTABILITY DOWNSTREAM OF CYCLIN E1 IN HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP12.
Abstract AP17: MOLECULAR AND FUNCTIONAL HETEROGENEITY OF CANCER ASSOCIATED FIBROBLASTS IN HIGH-GRADE SEROUS OVARIAN CANCER
Authors: Hussain Ali , Voisin Veronique , Poon Stephanie , Meens Jalna , Dmytryshyn Julia , Paterson Josh , Bernardini Marcus , Bader Gary , Neel Benjamin G , Ailles Laurie E 
Published: June 2021

Abstract
High grade serous ovarian cancer (HGSC) is typically diagnosed at an advanced stage and the vast majority of patients relapse and die within 5 years of diagnosis. Significant clinical problems in HGSC include wide-spread abdominal dissemination of disease and chemotherapy resistance. Cancer-associated fibroblasts (CAFs) have been shown to play a role in promotion of cancer cell proliferation and invasion, and mediation of chemotherapy resistance. To interrogate the molecular properties of CAFs in HGSC we used fluorescence activated cell sorting to isolate CAFs directly from primary tumor samples and performed gene expression profiling. We found that patients stratify into two classes based on their CAF gene signatures: One with high expression of Fibroblast Activation Protein (FAP-High; FH) and one with low expression of FAP (FAP-Low; FL). FH CAFs express classical CAF genes whereas FL CAFs possesses a preadipocyte-like molecular signature. The FL phenotype has remained largely unnoticed as it is generally out-competed in vitro by FH cells when grown under classical CAF culture conditions. Patients from The Cancer Genome Atlas (TCGA), as well as from our own institute, can be stratified into FH and FL subtypes; in both cohorts patients with FH CAFs have a significantly shorter disease-free and overall survival. In vitro and in vivo functional assays performed with isolated CAFs of both types indicate that FH CAFs aggressively promote proliferation, invasion and therapy resistance of cancer cells, whereas FL CAFs do not. Finally, we identified TCF21, a transcriptional repressor, as a FL-specific transcription factor. Analysis of published TCF21 ChIP-Seq data indicates that TCF21 targets a large number of genes specific to FH CAFs. Overexpression of TCF21 in FH CAFs partially reversed their ability to promote cancer cell invasion and tumor growth. Our discovery of CAF heterogeneity in HGSC highlights the need to personalize patient treatment with respect to both cancer and stromal phenotypes. FH patients may benefit from inhibition of cancer-stroma interactions or from epigenetic modulators that reprogram cancer-promoting FH CAFs into the non-supportive FL state.
Citation Format: Ali Hussain, Veronique Voisin, Stephanie Poon, Jalna Meens, Julia Dmytryshyn, Josh Paterson, Marcus Bernardini3, Gary Bader, Benjamin G Neel, Laurie E Ailles. MOLECULAR AND FUNCTIONAL HETEROGENEITY OF CANCER ASSOCIATED FIBROBLASTS IN HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP17.
Abstract AP26: CANCER STEM CELLS: DISTINCT SEEDS FOR RECURRENT OVARIAN CANCER
Authors: Ahmed Nuzhat , Escalona Ruth , Kadife Elif , Leung Dilys , Kannourakis George 
Published: June 2021

Abstract
PURPOSE: The treatment of ovarian cancer (OC) with chemotherapy leaves resistant cancer cells which in a short time re-grow as recurrent cancer. A diverse array of resistance mechanisms for chemotherapy has been described but none have proven as viable targets in a clinical setting. Cancer stem cells (CSCs) are increasingly accepted as the putative mediators of chemoresistance and relapse of cancer. This study aimed to understand the molecular mechanisms involved with chemoresistance and recurrence by investigating the proteomic profile of ascites-derived tumor cells obtained from OC patients prior to (chemonaive, CN) and after chemotherapy treatments (recurrent, CR).
METHODS: Ascites collected from CN and CR OC patients diagnosed with advanced-stage serous OC were cultured using a novel in vitro method to obtain a distinct population of epithelial tumor cells. Flow cytometry and immunofluorescence were used to characterize the tumor population. High-resolution label-free quantitative proteomic profiling was used to define significantly differentially expressed proteins between CN and CR tumor cells. KEGG and DAVID software's were used to determine pathways associated with CR cells. The mechanisms of survival of cisplatin and paclitaxel-treated OC cancer cells were determined in vitro by mRNA analysis and in vivo mouse xenograft models by immunohistochemistry.
RESULTS: Proteomic profiling of CN and CR tumor cells showed significant differences in proteins encoding for CSC, immune surveillance, DNA repair mechanisms, cytoskeleton rearrangement, cell-cell adhesion, cell cycle pathways, cellular transport, and proteins involved with glycine/proline/arginine synthesis in tumor cells isolated from CR relative to CN patients. Pathway analyses revealed enrichment of chemoresistance markers, energy metabolism, DNA repair mechanisms and immune surveillance pathways in recurrent CR tumor cells. Validation of these pathways in OC cell lines and nude mice treated with chemotherapy demonstrated increased expression of CSC and chemoresistant markers, enhancement in glycolytic pathway and oxidative phosphorylation, suppression of immune surveillance in chemotherapy treated cell lines and recurrent mice xenografts compared to untreated control.
CONCLUSION: These findings unravel some of the molecular mechanisms by which chemoresistance and relapse occur in OC patients' post-chemotherapy treatment; and may be important in designing novel therapeutic options for advanced-stage OC patients.
Citation Format: Nuzhat Ahmed, Ruth Escalona, Elif Kadife, Dilys Leung and George Kannourakis. CANCER STEM CELLS: DISTINCT SEEDS FOR RECURRENT OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP26.
Abstract AP31: ATR INHIBITION TARGETS TREATMENT RESISTANT OVARIAN CANCER
Authors: Kim Hyoung , George Erin , Xu Haineng , Medvedev Sergey , Jagannathan Veena , Morgan Mark , Mills Gordon , Brown Eric , Simpkins Fiona 
Published: June 2021

Abstract
Introduction: Although new treatments for ovarian cancer have been developed with the introduction of Poly (ADP-ribose) polymerase inhibitors (PARPi) to standard of care platinum chemotherapy, the majority of tumors acquire drug resistance. Strategies to circumvent PARPi and platinum resistance are needed and our study addresses this gap. We hypothesize that PARPi resistant tumors are dependent on ATR/CHK1 for DNA repair, and by targeting ATR in combination with PARPi would be more effective in eradicating tumor growth.
Experimental Procedures: Drug resistant cells were developed by long term treatment of PEO1 (BRCA2 mutant) and JHOS4 (BRCA1 mutant) ovarian cancer cells with PARPi (AZD2281) or Carboplatin. Cell viability, colony formation, cell cycle and apoptosis were evaluated. Homologous recombination was evaluated by Rad51 foci immuno staining. Replication fork asymmetry was counted by DNA combing assay. PARPi resistant orthotopic PDX models (germline BRCA1/ 2 mutant) were developed by long term treatment with PARPi. PDX developed from a platinum-resistant HGSOC patient with CCNE1 amplification was also tested to evaluate PARPi +/- ATRi. Whole genome sequencing, Reverse-Phase Protein Array Analysis (RPPA) and IHC were performed on cells and xenografts to evaluate for biomarkers of response.
Results: ATR/CHK1 pathway was constitutively activated in treatment resistant cell lines. Monotherapy with ATRi alone in vitro modestly induced cell death and DNA damage in PARPi and platinum resistant cell lines. Treatment with ATRi in combination with PARPi is synergistic in reducing survival of these drug resistant cells. Combination treatment was more effective in targeting cell cycle mediators, and promoting apoptosis. HR was restored in PARPi and platinum treatment resistant PEO1 cells. ATRi treatment suppressed restored HR and increased stalled replication fork. PARPi and ATRi combination treatment was synergistic in causing tumor regression in PARPi/Carboplatin resistant PDX models.
Conclusions: Our work suggests treatment resistant cells are more dependent on ATR/CHK1 pathway and ATR is a promising target for augmenting PARPi and platinum response in treatment resistant HGSOCs.
Citation Format: Hyoung Kim, Erin George, Haineng Xu, Sergey Medvedev, Veena Jagannathan, Mark Morgan, Gordon Mills, Eric Brown, Fiona Simpkins. ATR INHIBITION TARGETS TREATMENT RESISTANT OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP31.
Abstract DP-015: BIOTINYLATED ESTROGENS A NOVEL TOOL FOR EARLY DETECTION OF ADDUCT IN OVARIAN CANCER
Authors: Tripathi Kaushlendra , Mani Chinnadurai , Clark David W. , Palle Komaraiah 
Published: June 2021

Abstract
Elevated estrogens exert their carcinogenic effects by at least three different mechanisms; they promote cell proliferation by transcriptional regulation of estrogen responsive genes, cause generation of reactive oxygen species and other free radicals, and directly react with DNA and form potentially mutagenic adducts. However, unbalanced estrogen metabolism has been linked to development of several malignant diseases including breast, endometrial and ovarian cancer and has been identified as a risk factor for these cancers. The metabolic breakdown of estogens is regulated by a series of reactions mediated by hepatic and peripheral enzymes that balances the induction and reduction of cellular stress. An imbalance in this enzymes and processes can lead to highly reactive catechol estrogen metabolites that can react with DNA, form carcinogenic DAN-adducts and lesions. Although several studies established a connection between estrogen-induced DNA damage and carcinogenesis, the underlying molecular mechanisms have been difficult to study because of the technical challenges in detecting and analyzing the variety of different DNA lesions that are formed by estrogen compounds. Moreover, detection and analysis of these adducts are important to directly monitor estrogen metabolites induced cellular responses in the cells. Towards this, we developed a novel method using biotinylated-estrogens that allows immunodetection of estrogen-induced DNA adducts by Slot-blot and single-cell molecular combing and proximity ligation assays. Using these modified estrogens we first time quantitatively detected these adducts on DNA by immune Slot-blot techniques and on DNA fibers. Furthermore, similar to other environmental carcinogens estrogens activates replication associated DNA damage responses and induces chromosomal instability. Hence, first time our studies demonstrate that biotin-labeled estrogens could be a powerful tool to detect estrogen adducts and to probe associated DNA damage responses and cellular responses.
Citation Format: Kaushlendra Tripathi, Chinnadurai Mani, David W. Clark, Komaraiah Palle. BIOTINYLATED ESTROGENS A NOVEL TOOL FOR EARLY DETECTION OF ADDUCT IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-015.
Abstract GMM-026: AMPLIFICATION OF USP13 DRIVES OVARIAN CANCER METABOLISM
Authors: Han Cecil 
Published: June 2021

Abstract
Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis. The USP13 gene is co-amplified with PIK3CA in 29.3% of high-grade serous ovarian cancers and its overexpression is significantly associated with poor clinical outcome. Inhibiting USP13 remarkably suppresses ovarian tumor progression and sensitizes tumor cells to the treatment of PI3K/AKT inhibitor. Our results reveal an important metabolism-centric role of USP13, which may lead to potential therapeutics targeting USP13 in ovarian cancers.
Citation Format: Cecil Han. AMPLIFICATION OF USP13 DRIVES OVARIAN CANCER METABOLISM [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-026.
Abstract GMM-045: PAX8 PLAYS AN ESSENTIAL ROLE IN HIGH GRADE SEROUS OVARIAN CANCER VIA ACTIVATION OF MUTANT P53 AND MISLOCALIZED P21
Authors: Ghannam Dima , Jacob Eyal , Kakun Reli , Wasserman Tanya , Korsensky Lina , Sternfeld Ofir , Kagan Julia , Bublik Debora Rosa , Aviel-Ronen Sarit , Levanon Keren , Sabo Edmond , Larisch Sarit , Oren Moshe , Hershkovitz Dov , Perets Ruth 
Published: June 2021

Abstract
High grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer, and a very deadly disease, mostly due to lack of early detection methods. Wide spread disease at diagnosis has delayed the understanding that it often originates from the fallopian tube. This novel understanding has led to increased interest in fallopian tube developmental lineage markers, such as PAX8. In the adult fallopian tube, PAX8 is expressed in the fallopian tube secretory epithelial cell (FTSEC) and its expression is maintained through the process of FTSEC transformation Serous Tubal Intraepithelial Carcinoma (STIC) and to HGSC. We show that PAX8 has an essential pro-proliferative and anti-apoptotic role in HGSC. This role is mediated through direct transcriptional activation of mutated TP53, which often carries missense mutations that potentially lead to gain of function (GOF) oncogenic activities. Surprisingly, mutant p53 binds the p21 promoter and transcriptionally activates the expression of p21, which localizes to the cytoplasm of cells where it plays a non-canonical, pro-proliferative role. While in normal fallopian tube p21 is nuclear as expected, and STIC shows a mix of nuclear and cytoplasmic staining, an analysis of p21 staining in EOC shows that cytoplasmic p21 expression correlates with bad prognostic factors. Together, our findings illustrate that in HGSC TP53 mutations and abnormal p21 localization subvert a normal developmental pathway into a driver of tumor progression.
Citation Format: Dima Ghannam, Eyal Jacob, Reli Kakun, Tanya Wasserman, Lina Korsensky, Ofir Sternfeld, Julia Kagan, Debora Rosa Bublik, Sarit Aviel-Ronen, Keren Levanon, Edmond Sabo, Sarit Larisch, Moshe Oren, Dov Hershkovitz, Ruth Perets. PAX8 PLAYS AN ESSENTIAL ROLE IN HIGH GRADE SEROUS OVARIAN CANCER VIA ACTIVATION OF MUTANT P53 AND MISLOCALIZED P21 [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-045.
Abstract GMM-055: BMI1 AND RING1A ARE INVOLVED IN H2A UBIQUITINATION AT SITES OF PLATINUM-INDUCED DAMAGE
Authors: Sriramkumar Shruthi , O'Hagan Heather M. 
Published: June 2021

Abstract
Ovarian cancer is the 5th leading cause of death among women with the five year survival rate for ovarian cancer patients being only 46%. The standard of care for treatment of ovarian cancer patients is debulking surgery followed by platinum-taxane based chemotherapy. However, the major obstacle in the treatment of these patients with platinum based agents is development of chemoresistance. The platinum agents, cisplatin and carboplatin damage DNA by forming adducts with adjacent guanines, a high density of which are found in the promoter CpG islands of genes. Aberrant promoter DNA hypermethylation of genes and their subsequent transcriptional repression has been associated with development of cisplatin resistance. However, the mechanism of initiation of this aberrant DNA methylation and subsequent transcriptional repression is not known. Our overall hypothesis is that platinum induced DNA damage or repair of the damage leads to recruitment of repressive proteins to sites of damage. These repressive proteins transiently repress transcription in vicinity of damage to promote repair. However, similar to our findings with enzyme induced double strand breaks, repressive proteins may be retained at some key loci causing persistent transcriptional repression and gene silencing contributing to the development of platinum resistance. Our preliminary data demonstrates that BMI1, a member of polycomb repressive complex 1, localizes to sites of damage after cisplatin treatment. We also observe mono-ubiquitination of H2AX after cisplatin treatment and we hypothesize that this ubiquitination is occurring on K119. Mono-ubiquitination of H2A/H2AX at K119 has been associated with transcriptional repression and gene silencing during development and differentiation and also during repair of ionizing radiation and enzyme induced double strand breaks. Our data suggests that knockdown of RING1A reduces the cisplatin induced H2AX ubiquitination. We are currently determining which repair pathways and/or proteins result in recruitment of BMI1, RING1A to sites of damage. Importantly, after acute cisplatin treatment we also observe a reduction in expression of candidate genes which are known to be methylated in cisplatin resistant cells. We plan to determine if RING1A mediated ubiquitination is responsible for reduction in expression of target genes after acute cisplatin treatment and their methylation in cisplatin resistant cells. Understanding the mechanism of platinum induced gene silencing will enable us to design therapies to avert the development of drug resistant ovarian cancers.
Citation Format: Shruthi Sriramkumar, Heather M. O'Hagan. BMI1 AND RING1A ARE INVOLVED IN H2A UBIQUITINATION AT SITES OF PLATINUM-INDUCED DAMAGE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-055.