bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A005: Alanine metabolism is an ARID1A-dependent vulnerability in clear cell ovarian carcinoma
Authors: Nie Hao , Zhou Wei , Wang Chen , Zhang Nan , Wu Shuai , Zhang Rugang 
Published: March 2024

Abstract
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 alanine transporter SLC38A2 synergizes with immune checkpoint blockade (ICB) in ARID1A-inactivated OCCCs. Unbiased metabolic profiling revealed that alanine levels were increased by ARID1A inactivation in OCCC cells. In addition, using genome-wide approaches, we discovered that SWI/SNF inactivation downregulates SLC7A8 that is responsive for alanine secretion, while upregulating SLC38A2 that uptakes alanine extracellularly. This creates a dependence on the alanine consumption in ARID1A-inactivated cells. Inhibition of SLC38A2 reduces alanine uptake, impairs mitochondrial respiration, and induces cell cycle arrest and ARID1A inactivation exacerbates these effects. SLC38A2 inhibition suppresses the growth of ARID1A mutant, but not wildtype, OCCCs. In addition, SLC38A2 inhibition synergizes with anti-PD-L1 antibody in a genetic OCCC mouse model driven by conditional ARID1A inactivation. Our data indicate that inhibition of the alanine metabolism simultaneously suppresses tumor cell growth and boosts antitumor immunity, which synergizes with immune checkpoint blockade in suppressing ARID1A-mutated cancers.
Citation Format: Hao Nie, Wei Zhou, Chen Wang, Nan Zhang, Shuai Wu, Rugang Zhang. Alanine metabolism is an ARID1A-dependent vulnerability in clear cell ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A005.
Abstract A033: The transcriptional landscape of cisplatin resistance and its relationship with epithelial mesenchymal transition in ovarian cancer
Authors: Suzuki Tise , Chen Wanqiu , Wang Charles , Unternaehrer Juli 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSOC) remains the deadliest cancer of the female reproductive system. Among the many treatment alternatives, platinum-based therapies have been ubiquitous. However, even though initial response is favorable, most patients experience relapse and chemoresistance. Many studies have highlighted the role of epithelial-mesenchymal transition (EMT) in contributing to chemoresistance. In fact, the EMT transcription factor SNAI1 (Snail) has been associated with the development of aggressive disease. Nevertheless, further studies are necessary to understand the underlying mechanisms by which Snail contributes to recurrence and resistance. Thus, our goal is to develop a clinically relevant model of chemoresistance in which to study the transcriptional landscape and gene signatures related to EMT, platinum resistance, and recurrence in HGSOC. After acquisition and characterization of a HGSOC patient sample, cells were continuously exposed to increasing concentrations of cisplatin in vitro, until approximately a tenfold increase in IC-50 relative to parental cells was achieved. RNA-seq analysis comparing the patient-derived sensitive and resistant cell line pair identified over 4,000 genes that were differentially expressed. Furthermore, gene expression was evaluated against a database of genes associated with platinum resistance, revealing 273 genes linked with mechanisms of apoptosis, extracellular matrix signaling, immune response, cancer stemness, EMT, among others. Additionally, we analyzed previously published chromatin immunoprecipitation-sequencing (ChIP-seq) studies for Snail to determine the potential mechanism of EMT-induced therapy resistance. Our results indicate that most of the genes associated with platinum resistance mechanisms were identified by more than two Snail ChIP-seq studies, indicating their potential for being regulated. Furthermore, to establish whether such genes could also be regulated in HGSOC, we compared our findings to ATAC-seq studies done in ovarian cancer cell lines. Data obtained from these analyses will be used in the future assessment of Snail’s direct regulation of these pathways and functions.
Citation Format: Tise Suzuki, Wanqiu Chen, Charles Wang, Juli Unternaehrer. The transcriptional landscape of cisplatin resistance and its relationship with epithelial mesenchymal transition in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A033.
Abstract A084: AMH paracrine signaling between cancer and mesothelial cells modulates the ovarian tumor immune microenvironment
Authors: Chauvin Maeva Y. 
Published: March 2024

Abstract
Introduction: Cancer-associated mesothelial cells (CAMCs) have emerged as significant contributors to the tumor microenvironment, influencing tumor growth and immune evasion. Mesothelial cells represent the first point of contact of ovarian cancer cells during their peritoneal spread. Normal omental mesothelial cells have been reported to play a role in immune surveillance of the peritoneal cavity. However, beyond their initial involvement during the seeding of cancer cells to the omentum, the role of omental mesothelial cells in the subsequent development of the tumor microenvironment and the immune evasion of the tumor remains poorly understood. Methods: To study the role of mesothelial cells in the tumor microenvironment, we recently generated novel syngeneic mouse models of high grade serous ovarian cancer, which were derived from Fallopian tube epithelium, and bear human-relevant mutational genotypes. We analysed one such model, the CCNE1-amplified KPCA cell line, using single cell transcriptomics in omental metastases to survey the pattern of expression of the anti-Müllerian hormone (Amh) and its receptor Amhr2 across tumor cell types. Results: Single-cell transcriptomics revealed specific expression of Amhr2 in cancer-associated mesothelial cells, but not normal omental mesothelium. The co-culture of cancer cells with normal omental mesothelial cells induced AMHR2 expression along with a pro-tumorigenic cancer-associated mesothelial cell transcriptomic signature. Overexpression of AMHR2 in a human immortalized mesothelial cell line (Met5a) significantly modulated the expression of genes involved in immune response pathways, remodeling of extra-cellular matrix, and secretion of growth factors. Furthermore, we showed that AMH was secreted by ovarian cancer cells and downregulated key immunomodulatory cytokines (Ccl2, Cxcl2/3, Il1a/b) secreted by CAMCs, thus promoting immunosuppression within the tumor. Finally, implantation of ovarian cancer cells into syngeneic Amhr2−/− hosts produced tumors that grew significantly slower than in wild type hosts, which contained significantly reduced populations of exhausted T cells as marked by PD1 and CTLA4 expression. Conclusion: Together these data suggest that AMHR2 expression is necessary for the reprogramming of mesothelial cells into CAMCs and represents a specific marker of CAMCs in ovarian cancer. The AMH-AMHR2 paracrine axis between cancer cells and CAMCs modulates the tumor microenvironment to promote growth and immune evasion and may represent a novel target for immunotherapy in ovarian cancer.
Citation Format: Maeva Y. Chauvin. AMH paracrine signaling between cancer and mesothelial cells modulates the ovarian tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A084.
Abstract A088: Tumor innervation as a novel driver of ovarian cancer progression
Authors: Knarr Matthew , Reavis Hunter , Lippert Timothy , Rawat Priyanka , Vermeer Paola , Drapkin Ronny 
Published: March 2024

Abstract
One of the main challenges currently faced in ovarian cancer treatment is that the primary platinum/taxane therapy used to treat patients does not meaningfully extend survival. The overall survival for ovarian cancer patients with advanced disease is less than 30% with most patients recurring within 5 years of initial therapy. Once resistant disease develops there are few second line therapy options, which inevitably leads to disease progression. Thus, there is a critical need to identify new therapies that can overcome ovarian cancer chemoresistance and produce meaningful increases in patient survival. In recent years, new efforts have focused on targeting the tumor microenvironment (TME), the complex mixture of non-cancer cells that surround and support the cancer cells within the tumor. Different strategies have evolved to target the TME, such as immune checkpoint inhibitors or angiogenesis inhibitors. However, these TME targeting therapies have limited effect when used to treat ovarian cancer patients. Most ovarian tumors have a microenvironment that is highly immunosuppressive and do not respond or are resistant to angiogenesis inhibitors. Thus, new TME targeting therapies must be developed that can induce a therapeutic effect in ovarian tumors and can be used to treat most ovarian cancer patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors in a process termed tumor innervation. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains undefined. Here we show that Transient Receptor Potential cation channel subfamily V member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer growth and metastasis. Analysis of patient samples shows that sensory nerve fiber innervation is much higher in ovarian tumors vs benign reproductive tissue. In addition, ablation of TRPV1 sensory nerve fibers in vivo causes reduced tumor burden and prolongs survival in a syngeneic mouse model of ovarian cancer metastasis. Taken together, our results establish TRPV1+ sensory innervation as a novel driver of ovarian cancer growth/metastasis and a potential therapeutic target for ovarian cancer treatment.
Citation Format: Matthew Knarr, Hunter Reavis, Timothy Lippert, Priyanka Rawat, Paola Vermeer, Ronny Drapkin. Tumor innervation as a novel driver of ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A088.
Abstract A101: A novel ovarian cancer organotypic tumor slice culture model
Authors: Pourcel Violaine , Létourneau Emile , Jean Dominique , Labrie Marilyne 
Published: March 2024

Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most common form of ovarian cancer (OC). This heterogeneous disease is associated with various molecular alterations influencing the disease course. Unfortunately, the impact of those molecular alterations on the response to therapy is still misunderstood. Few OC models allow control of genetic background in the cancer cells while preserving the tumor's architecture and microenvironment, including the immune cells. Furthermore, there is currently no high-throughput model that retains those characteristics and is suitable for drug screens. This project aims to develop a high-throughput syngeneic murine organotypic tumor slice culture model to study the impact of common HGSOC molecular alterations on anticancer drug responses. The pre-established Trp53−/− syngeneic OC mouse model has been genetically engineered to represent molecular alterations frequently found in HGSC. Ten variants were produced by overexpressing Tp53R172h and overexpressing oncogenes such as Ccne, Brd4, Myc, Ndrg1, and Pik3ca and/or deleting Brca1, Pten, and Nf1. After validation and characterization of the cells in vitro, we performed allografts in immunocompetent C57/bl6 mice and obtained tumors with HGSOC histology. The tumors were used to develop an organotypic tumor slice culture model. Briefly, each tumor is collected and thinly sliced with a vibratome. Each slice can be cultured for several days without significant cell death induction and can be used for a drug screen. Our preliminary data shows that the model preserves the HGSOC histology over six days and remains viable. A viability assay has also been developed to assess the sensitivity of the tumor slices to various anticancer drugs. In conclusion, this project will allow the development of a platform for screening anticancer therapies against HGSOC and will lead to a better understanding of the relationship between HGSOC's common molecular alterations and the responses to therapy.
Citation Format: Violaine Pourcel, Emile Létourneau, Dominique Jean, Marilyne Labrie. A novel ovarian cancer organotypic tumor slice culture model [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A101.
Abstract A114: Robust establishment and expansion of multilineage human fallopian tube organoids in serum-free medium
Authors: Ho Victor , Chan Maggie , Chehal Manreet , Liang Alice , Eaves Allen C , Louis Sharon A , Stingl John 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of epithelial ovarian cancer. Despite its name, HGSOC originates in the fallopian tube (FT), but metastasizes quickly in the adnexal region and is the most lethal gynecological cancer worldwide. Organoid culture is emerging as a powerful model for studying normal FT cell biology and ovarian cancer. To standardize primary human FT and HGSOC organoid culture, we have developed GyneCult Fallopian Tube Organoid Medium (FTOM), an optimized serum-free medium and a workflow that supports robust and representative FT organoid culture from freshly isolated or cryopreserved primary human FT cells. FT cultures were initiated by seeding 4000 fresh or cryopreserved single cells (8 donors) directly into 20 µL Corning® Matrigel® domes and overlaying them with FT Organoid Medium. Cultures were maintained with full-medium changes every 3 - 4 days and were passaged every 8 - 14 days into new 20 µL Matrigel® droplets, either at a passage ratio of 1:3 or by seeding at 4000 cells per droplet. Cultures were analyzed by immunocytochemistry (ICC) to detect secretory markers keratin 7 (KRT7), oviductal glycoprotein 1 (OVGP1), and PAX8, as well as ciliated cell markers acetylated alpha tubulin (TUBA1A) and FOXJ1. Across all donors, 16 ± 8% (mean ± SD) of dissociated EpCAM+ FT cells formed 50 - 300 µm diameter cystic organoids within 14 days of seeding (n = 8). Cultures can be maintained for at least 5 passages with 14 - 20 cumulative population doublings, at 3 - 4 doublings per passage. ICC analysis confirmed that organoids contained both polarized secretory cells (i.e., KRT7+, OVGP1+, PAX8+) and ciliated cells (i.e. acetylated TUBA1A+, FOXJ1+), indicating multilineage capacity (n = 5). We also tested the compatibility of GyneCult FTOM with culturing HGSOC samples and observed that one of three tumor samples tested generated organoids. These tumour organoids had a solid and irregular shaped morphology and were composed of PAX8+ cells. These cells underwent ≥ 5 cumulative population doublings over 5 passages, with 0.5 - 2 doublings per passage; this performance is consistent with recently published HGSOC organoid culture methods. These results demonstrate that GyneCult Fallopian Tube Organoid Medium is a robust medium for initiating and culturing FT epithelium as organoids, can support HGSOC organoid culture, and is a valuable tool for studying FT biology.
Citation Format: Victor Ho, Maggie Chan, Manreet Chehal, Alice Liang, Allen C Eaves, Sharon A Louis, John Stingl. Robust establishment and expansion of multilineage human fallopian tube organoids in serum-free medium [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A114.
Abstract B003: A multi-omic analysis to identify epigenetic drivers of platinum-resistance in high-grade serous ovarian carcinoma models
Authors: Adams Kristin , Moreno Ryan , Wendt Jae-Rim , Wood Josie , Roopra Avtar , Lang Jessica D. 
Published: March 2024

Abstract
Despite being rare cancers, ovarian cancer rank as the fifth leading cause of cancer mortalities in women in the United States. Most patients are detected late, with most patients diagnosed in Stages 3 and 4. While patients often initially respond to standard of care chemotherapy, which includes platinum-based chemotherapy such as cisplatin and carboplatin, they recur with resistant phenotypes. While a large effort has characterized mechanisms of resistance to platinum-based chemotherapy, it is still challenging to identify these patients and identify more promising therapies. While the field understands that a quiescent, stem cell-like state can serve as an intermediate from which chemoresistant recurrences can arise, the epigenetics of this state are less well understood. In fact, we do know that embryonic and pluripotent stem cells differ significantly in enhancers and other epigenetic features that contribute significantly to their phenotypes. We performed histone post-translational modifications by CUT&Tag, as well as ATACseq and RNA-seq, on four isogenic cell line models of cisplatin resistance. We show that these models are resistant to both cisplatin and carboplatin. While we see paradoxical quiescent cell markers in these isogenic lines, we have characterized differential features of their epigenetics that may contribute to the resistant phenotype. We are continuing to explore transcription factors that may drive this resistance. We are also examining super-enhancers that are altered between chemo-sensitive and -resistant cell lines. Similarly, we have examined whether inhibitors of components of super-enhancers may be a viable therapeutic option for platinum-resistant high-grade serous ovarian cancer patients. We see moderate synergy between triptolide (targets TFIIH subunit XPB1) and JQ-1 (targets BRD4) with cisplatin in resistant models. Together, we hope our studies can contribute to the knowledge of how epigenetic features might contribute and be targets for chemoresistance in ovarian cancer.
Citation Format: Kristin Adams, Ryan Moreno, Jae-Rim Wendt, Josie Wood, Avtar Roopra, Jessica D. Lang. A multi-omic analysis to identify epigenetic drivers of platinum-resistance in high-grade serous ovarian carcinoma models [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B003.
Abstract B007: NAD+ metabolism drives PARPi resistance in ovarian cancer cells
Authors: Myong Subin , Shah Hardik , Nagele Benedikt , Rajesh Reshma , Challa Sridevi 
Published: March 2024

Abstract
NAD+ is a coenzyme for redox reactions and a cofactor for enzymes such as PARPs and Sirtuins. The nuclear enzyme PARP1 is a major consumer of NAD+, which is cleaved during the catalytic activation of PARP1 in response to DNA damage. PARP1 inhibitors compete with NAD+ for the catalytic site of PARP1 and reduce the catalytic activity of PARP1 and impair DNA damage repair. Recently PARP inhibitors (PARPi) have shown efficacy in the treatment of ovarian cancers and most patients with defects in homologous repair of DNA damage are now on PARPi maintenance. But, heterogeneous responses to PARPi is limiting their clinical efficacy. To identify the mechanisms of PARPi resistance, we generated a panel of ovarian cancer cells with acquired resistance to niraparib (PARPiR), an FDA approved PARP inhibitor. We demonstrated that the PARPiR cells are also resistant to other FDA approved PARP inhibitors rucaparib and olaparib. This data suggested that a common mechanism of resistance underlies poor response to the FDA approved PARP inhibitors. Since PARP1 activity is tightly controlled by the cellular NAD+ levels, we next investigated the role of NAD+ biosynthesis in PARPi resistance. Metabolomic profiling of the parental and PARPiR cells demonstrated that PARPiR cells have elevated levels of NAD+ metabolism. Indeed, treating the PARPiR cells with inhibitors of NAD+ synthesis restored the sensitivity to PARP inhibitors. Moreover, culturing the previously sensitive parental ovarian cancer cells in NAD+ precursors decreased their sensitivity to PARP inhibitors. These data collectively demonstrated that high levels of NAD+ metabolism causes PARP inhibitor resistance in ovarian cancer cells. Complementary to the metabolomic analysis, results from phenotypic assays in PARPiR cells revealed that high levels of NAD+ maintain cellular quiescence in PARPiR cells. In summary, our results demonstrated that high levels of NAD+ biosynthesis causes PARPi resistance by maintaining cellular quiescence. There is an urgent need to identify the mechanisms of resistance to PARP inhibitors to increase their clinical efficacy. Our study identified that maintenance of quiescence is a fundamental mechanism of PARPi resistance. We also demonstrated that inhibiting NAD+ biosynthesis reverses PARP inhibitor resistance.
Citation Format: Subin Myong, Hardik Shah, Benedikt Nagele, Reshma Rajesh, Sridevi Challa. NAD+ metabolism drives PARPi resistance in ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B007.