bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract GMM-061: MOLECULAR CHARACTERIZATION OF MOUSE MODELS OF HIGH-GRADE SEROUS CARCINOMA ARISING IN THE OVIDUCT
Authors: Zhai Yali , Wang Yisheng , Schulman Stephanie M. , Hu Kevin , Liu Albert , Tomlins Scott A. , Fearon Eric R. , Cho Kathleen R. 
Published: June 2021

Abstract
We recently developed genetically engineered mouse models (GEMMs) of oviductal high-grade serous carcinoma (HGSC) based on conditional inactivation of several different combinations of tumor suppressor genes (Brca1, Trp53, Rb1, and Nf1) that are recurrently mutated in human HGSCs. The histopathological features of the mouse tumors closely mimic their human tumor counterparts. In order to characterize how well the mouse tumors recapitulate the molecular characteristics of human HGSCs, targeted exome sequencing was used to analyze the 32 most commonly mutated genes in human HGSC, in 60 mouse tumors arising in the context of Brca1, Trp53, Rb1, and/or Nf1 inactivation. We employed the sequence data to assess DNA copy number alterations (CNAs) and single nucleotide variants (SNVs) in the mouse tumors.
Compared to 14 normal tissues and 8 oviductal tumors arising in the context of Apc, Pten, ± Arid1a inactivation, the mouse HGSCs showed a high level of genomic instability, with many widely distributed CNAs – very similar to the widespread CNAs observed in human HGSCs. Targeted exome sequencing also showed that a subset of the mouse tumors acquired alterations observed in human HGSCs, including amplification of cMyc, and deletion of Pten. Variant analysis identified nonsynonymous SNVs in Csmd3, Crebbp, Pten, Mettl17, and Zymynd8 and a frameshift deletion of Pten. Sanger sequencing confirmed the presence of these somatic mutations in the mouse tumors and their absence in matched normal tissues. Loss of PTEN expression was observed in those tumors that acquired somatic Pten alterations.
These data show that HGSCs arising in our GEMMs have very similar molecular characteristics to their human tumor counterparts. The somatic alterations are likely acquired during the relatively lengthy period (several months) between tumor initiation and progression to overt malignancy. These features render the models particularly well suited for studying the early phases of HGSC development and for translational applications aimed at identifying effective strategies for HGSC prevention and early detection.
Citation Format: Yali Zhai, Yisheng Wang, Stephanie M. Schulman, Kevin Hu, Albert Liu, Scott A. Tomlins, Eric R. Fearon, and Kathleen R. Cho. MOLECULAR CHARACTERIZATION OF MOUSE MODELS OF HIGH-GRADE SEROUS CARCINOMA ARISING IN THE OVIDUCT [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-061.
Abstract NT-091: TGF-β1-INDUCED CHEMORESISTANCE IS REVERSED BY BG-4 PEPTIDE
Authors: Dia Vermont P 
Published: June 2021

Abstract
Transforming growth factor-β (TGF-β) superfamily plays a significant role in ovarian physiology but dysregulated TGF-β signaling is associated with promotion of ovarian carcinogenesis. TGF-β signaling in ovarian cancer favors cancer invasion and metastasis and controls ovarian cancer cell proliferation. The objective of this study is to determine the ability of a food-derived peptide, called BG-4, to suppress TGF-β1 signaling in ovarian cancer cells. BG-4 is a novel bioactive peptide isolated from the seeds of Momordica charantia with demonstrated anticancer and strong trypsin inhibitory properties. Different ovarian cancer cells (A2780-1A9, BR and PEO4) were exposed to 10 ng/mL TGF-β1 with or without non-cytotoxic dose of BG-4 (100 µg/mL) and response to chemotherapeutic reagents paclitaxel and cisplatin was evaluated. In addition, markers of epithelial-to-mesenchymal transition (EMT) and apoptosis were evaluated using western blot and immunofluorescence microscopy. TGF-β1 treatment resulted in cisplatin resistance in three cell lines as evidenced by increase in ED50 values from 42.9 µM to 88.5 µM, 53.7 µM to 108.3 µM and 44.8 µM to 67.3 µM for BR, PEO4 and A2780-1A9 cells, respectively. In the presence of BG-4, ED50 values of 35.6 µM, 56.4 µM and 46.6 µM were obtained for BR, PEO4 and A2780-1A9 cells, respectively. These values are similar to non-TGF-β1-treated cells indicating the ability of BG-4 to reverse TGF-β1-induced chemoresistance in ovarian cancer cell lines. Mechanistic studies showed that TGF-β1 signaling induces EMT in ovarian cancer cells as shown by differential expression of epithelial marker E-cadherin and mesenchymal markers N-cadherin, vimentin and transcription factors Snail, Slug and Twist1. In addition, the expression of apoptosis markers were affected by TGF-β1 signaling. On the other hand, treatment of TGF-β1 in the presence of 100 µg/mL BG-4 led to reversal of the EMT process. These results showed that the ability of BG-4 to reverse TGF-β1-induced chemoresistance in ovarian cancer cell lines may be associated with inhibition of the EMT process.
Citation Format: Vermont P Dia. TGF-β1-INDUCED CHEMORESISTANCE IS REVERSED BY BG-4 PEPTIDE [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 NT-091.
Abstract NT-095: ERADICATION OF CHEMORESISTANT METASTATIC OVARIAN CANCER WITH IMMUNOTARGETED EPIGENOMIC NANOSURGERY (IEN)
Authors: Giannios John N. 
Published: June 2021

Abstract
INTRODUCTION: Resistance to conventional chemotherapy such as cisplatin, and radiotherapy in ovarian cancer may be caused by deregulated oncogenic miRNA-221/222 inhibiting induction of apoptosis.
METHODS: Chemoradioresistant cells overexpressing EphA2 were obtained for developing an ovarian metastatic cancer model, which was treated with anti-EphA2 MAbs immunotargeted pegylated nanosomes with encapsulated paired guide-RNAs targeting 3' and 5' of the precursor microRNA 221/222.
RESULTS: Post-treatment, the paired guide-RNAs caused deletions in the targeted pre-microRNA 221/222 genomic-sequences removing the stem-loop hairpins after blockade of RNase-III Drosha and DGCR8 (microprocessor-complex), subsequent transport by exportin-5/RanGTP and cleavage by Dicer inhibiting miRNA221/222 biogenesis, and miRNP circumventing their incorporation in RISC, and subsequent mRNA cleavage of coding genes regulating according to NGS the PTEN, GJA1, SEMA3B, TIMP3, PTPRM, CDKN1C, MGMT, CDKN1B, PUMA, connexin-43 (CX-43), c-Jun, MMP, NF-kB, PI3K, p27/Kip1, PTPμ, NIAP, ICAM-1, STAT1, STAT2, STAT3/Akt, CDK4, CDKN1C/p57, p53, and p57 inhibiting metastatic ovarian cancer cell proliferation, chemo/radioresistance, migration, angiogenesis, invasion, metastasis and maintenance of MET expressing ovarian metastatic cancer stem cells, while inducing cytotoxic immune responses (CTLs), and D2 irreversible stage of apoptosis or programmed cell death type-I leading to a bystander killing effect (BKE) due to phagocytosis of adjacent tumor cells according to transmission electron micrographs.
CONCLUSION: Immunotargeted epigenomic nanosurgery may eradicate metastatic ovarian cancer after inhibition of oncogenic miRNA 221/222 expression, and downstream signaling pathways involving interactions with coding RNA genes leading to apoptosis or PCD type I and BKE after the circumvention of chemo/radioresistant mechanisms.
Citation Format: John N. Giannios. ERADICATION OF CHEMORESISTANT METASTATIC OVARIAN CANCER WITH IMMUNOTARGETED EPIGENOMIC NANOSURGERY (IEN) [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 NT-095.
Abstract TMIM-074: IGF2 IN HUMAN FOLLICULAR FLUID PROMOTES LYMPHOMAGENESIS IN MAMMARY FAT PAD OF TRP53-NULL MICE, DEPENDING ON ESTROGEN IN MICROENVIRONMENT
Authors: Huang Hsuan-Shun , Chu Sung-Chao , Chu Tang-Yuan 
Published: June 2021

Abstract
Ovulation overdrive is the most important risk factor of ovarian cancer. In previous study we discovered that preovulatory follicular fluid (FF) collected from IVF women, upon weekly injections into the mammary fat pad of Trp53-null mice for 7 weeks, could induce early onset of B cell lymphomas. In subsequent studies (Abstract by Chu TY et al.), we disclosed the IGF-axis signaling conferred by FFs is responsible for the stemness, clonal expansion and transformation of fallopian tube fimbrial epithelial cells where IGF2 in FF bound IGF-1R on secretory cells to activate the downstream PI3K/Akt/mTOR and PI3K/Akt/NANOG signaling pathways for the transformation.
In this study, we identified the same IGF2 is also responsible for the FF-induced lymphomagenesis in Trp53-null mice. When IGF2 was depleted from FF, the tumorigenesis rate reduced from 10/18 (56%) to 1/6 (17%). On the other hand, injections with pure IGF2 (100 mg/ml) grew tumors in 33% (2/6) of mice. The same injection to Trp53 wild type did not grow tumor.
We also found a microenvironment of adipose tissue seemed to be important for the FF-induced lymphomagenesis. The same injections of FF into the subcutis and other sites did not grow tumor.
Additionally, tumor development depends not only on the injection site but also on the female sex hormone and ER function. No tumor growth was observed in castrated female mice and in male mice. Adding fulvastrant to the injections resulted in complete shrinkage of tumor. Meanwhile, extended injection of FF from 7 weeks to 13 weeks promoted tumor progression but did not increase tumor incidence.
The findings suggest a transformation activity of human preovulatory FF largely conferred by IGF2. In the context of germline Trp53 loss, this activity likely promotes expansion of the lymphocytic progenitors that have already been transformed. Meanwhile, we found ER is expressed in the tumor adjacent adipocytes but not in the lymphoma cells. Also, ER antagonist, although largely confined tumor growth, did not decrease the tumor incidence. In this tumorigenesis model conferred by Trp53 loss and FF-IGF2, estrogen seems to play an essential role in tumor progression but not in tumor initiation, and this promotion effect is through the adipocyte microenvironment.
Citation Format: Hsuan-Shun Huang, Sung-Chao Chu, Tang-Yuan Chu. IGF2 IN HUMAN FOLLICULAR FLUID PROMOTES LYMPHOMAGENESIS IN MAMMARY FAT PAD OF TRP53-NULL MICE, DEPENDING ON ESTROGEN IN MICROENVIRONMENT [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 TMIM-074.
Abstract TMIM-081: THE HYPOXIC TUMOR-MESOTHELIAL NICHE PROMOTES OVARIAN CANCER METASTASIS THROUGH COLLAGEN REMODELING
Authors: Natarajan Suchitra , Foreman Katie , Soriano Michaela , Shehade Hussein , Fregoso Daniel , Eggold Joshua , Rosen Ninna S. , Heilshorn Sarah , Krieg Adam J. , Krishnan Venkatesh , Dorigo Oliver , Sinha Subarna , Fuh Katherine C. , Rankin Erinn B. 
Published: June 2021

Abstract
High grade serous ovarian cancer (HGSOC) is a leading cause of cancer related deaths among women. The primary cause of morbidity and mortality in HGSOC patients is metastasis to organs within the peritoneal cavity. Mesothelial cells line the surface of peritoneal organs and are a key stromal cell in HGSOC metastatic niche. However, the mechanisms by which mesothelial cells promote ovarian cancer peritoneal metastasis remain largely unknown. Here we demonstrate that tumor associated mesothelial cells promote tumor invasion by increasing collagen deposition and remodeling. Mechanistically, we demonstrate the tumor-mesothelial niche is hypoxic where both tumor cells and mesothelial cells express the hypoxia inducible factors HIF-1 and HIF-2 and their downstream target gene lysyl oxidase (LOX). LOX is an enzyme that crosslinks collagen fibrils to promote collagen remodeling. In tumor-mesothelial co-culture experiments, we demonstrate that hypoxia enhances extracellular fibrillar collagen deposition by mesothelial cells. Conditioned media from hypoxic tumor-mesothelial co-cultures promotes collagen remodeling and HGSOC tumor cell invasion. Genetic inactivation of either HIF-1 and HIF-2 or LOX reduces the hypoxic induction of collagen remodeling and tumor cell invasion. Importantly, pharmacologic inhibition of HIF-1 and HIF-2 with digoxin reduces the colonization of disseminated HGSOC cells to the omentum, the preferential migration site of peritoneal cancer metastasis. Moreover, pharmacologic inhibition of LOX with BAPN (beta-aminopropionitrile) is sufficient to inhibit metastatic tumor burden and collagen remodeling at metastatic sites in preclinical models of HGSOC metastasis. These data reveal a novel role for mesothelial cells in the production of type I collagen and collagen remodeling in the HGSOC metastatic microenvironment. Furthermore, these studies demonstrate a role for the HIF/LOX signaling axis in the HGSOC tumor-mesothelial niche that can be therapeutically targeted to inhibit collagen remodeling and ovarian cancer metastatic progression.
Citation Format: Suchitra Natarajan, Katie Foreman, Michaela Soriano, Hussein Shehade, Daniel Fregoso, Joshua Eggold, Ninna S. Rosen, Sarah Heilshorn, Adam J. Krieg, Venkatesh Krishnan, Oliver Dorigo, Subarna Sinha, Katherine C. Fuh, Erinn B. Rankin. THE HYPOXIC TUMOR-MESOTHELIAL NICHE PROMOTES OVARIAN CANCER METASTASIS THROUGH COLLAGEN REMODELING [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 TMIM-081.
Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History
Authors: Penter Livius , Gohil Satyen H. , Lareau Caleb , Ludwig Leif S. , Parry Erin M. , Huang Teddy , Li Shuqiang , Zhang Wandi , Livitz Dimitri , Leshchiner Ignaty , Parida Laxmi , Getz Gad , Rassenti Laura Z. , Kipps Thomas J. , Brown Jennifer R. , Davids Matthew S. , Neuberg Donna S. , Livak Kenneth J. , Sankaran Vijay G. , Wu Catherine J. 
Published: June 2021

AbstractWhile cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure, indicating clonal persistence, but dramatic changes following tight bottlenecks, including disease transformation and relapse posttherapy, paralleled by acquisition of copy-number variants and changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into nongenetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics.Significance:Single-cell multi-omic profiling of CLL reveals the utility of somatic mtDNA mutations as in vivo barcodes, which mark subclones that can evolve over time along with changes in accessible chromatin and gene expression profiles to capture dynamics of disease evolution.See related commentary by Hilton and Scott, p. 2965.This article is highlighted in the In This Issue feature, p. 2945
Abstract A17: Predictions of comparative clinical outcomes for checkpoint inhibitor combo therapies and mechanistic targets in first-line NSCLC
Authors: Vanderman Kadie , Stine Andrew , Chang Steven 
Published: June 2021

Abstract
The success of checkpoint inhibitors for immunotherapy has ushered in a new era of cancer treatment. While response rates of approximately 20% are observed with checkpoint monotherapy in NSCLC, it remains one of the most deadly forms of cancer. Combinatory therapy approaches have been rapidly implemented, with the selection of agents largely based on theoretical considerations (Kargl, 2017 #19227). The high number of new clinical trials of anti-PD1 with a combination therapy raises the concern that adequate patient enrollment may become a barrier to trial completion and approval. Hence, drug candidate selection and identification of patients most likely to benefit from treatment are emerging needs of the field. Further, irregularity in patient enrollment criteria and trial designs prevents the direct comparison of regimens, impeding clinical decision making. To address rationale immunotherapy decisions for first- line NSCLC patients, we developed a mechanistic, systems biology model to compare the efficacy of 4 candidate therapies in combinations with an anti-PD1 therapy. Our model captured mechanisms underlying the pro- and anti-inflammatory influences of the innate immune system on Tregs and T cell effector function. “Simulated patients” were then created based on patient level data of 30-60 baseline measurements from preclinical and clinical publications in squamous and nonsquamous NSCLC patients. The model permeated all vectors and combinations of data. Each unique set of permutations that fit within clinical monotherapy data from platinum doublet chemotherapy SOC, anti-PD1, anti-CTLA4, and EGFR inhibitor trials in NSCLC represented a simulated patient. Over 200 patients were simulated to create a virtual trial population. As a performance validation, our model blindly predicted the NSCLC results from published combination trials of anti-PD1 + CTLA4 and anti-PD1 + EGFR. The model then was used to predict results for an anti-PD1 + Lag3 and anti-PD1 + CCL2, for which no trial results are available. We conducted a direct comparison between the co-therapy regimens, controlling for trial design and using the same simulated patient population for each trial arm. The large and diverse simulated patient population allowed us to evaluate trends in the characteristics of the tumor microenvironment of differential responders/nonresponders on one regimen vs. another, such as the immune cell composition, biomarker levels, and cytokine levels.
Citation Format: Kadie Vanderman, Andrew Stine, Steven Chang. Predictions of comparative clinical outcomes for checkpoint inhibitor combo therapies and mechanistic targets in first-line NSCLC [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A17.
Abstract A54: Epigenetic activated IL1B promotes tumor progression of tongue cancer
Authors: Zheng Dali , Chen Weitao , Lu Youguang 
Published: June 2021

Abstract
Alterations in host immunity, inflammation, angiogenesis, and metabolism have been noted to be prominent clinical features in patients with head and neck squamous cell carcinoma (HNSCC). IL-1β, a prototypical inflammatory cytokine, is induced and activated following infection and tissue damage. High IL-1 levels in the tumor microenvironment are associated with a more aggressive tumor phenotype and generally poor prognoses. It was reported that single-nucleotide polymorphisms (SNPs) identified in IL1B gene influence the risk of many kinds of cancer, but the role of IL1B in the development and progress of HNSCC and the related molecular mechanism were not well understood. In the present study, we found IL1B was upregulated in tongue cancer tissues according to our RNA-Seq data and was validated in other 60 paired clinical samples. Using data from The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSC), we found that the expression of IL1B in HNSCC tumor samples (n=501) is significantly higher than the adjacent noncancer tissues (n=44) and hypomethylation of CpG sites was found around the promoter region of IL1B in the cancer samples. Regression analysis identified a moderately negative correlation between IL1B expression and the DNA methylation of these CpG sites, even though there is not CpG island around its promoter. Knockdown of IL1B in Cal-27 and TCA-8113 tongue cancer cells inhibited cell proliferation, migration and invasion ability, and overexpression of IL1B or recombinant IL1B protein can promote proliferation, migration and invasion of tongue cancer cells. The results indicated that aberrant IL1B expression might be modulated by its DNA hypomethylation and IL1B produced by cancer cells can promote tumor progression and metastasis, and the inhibition of IL1B pathway may be a novel therapeutic approach in the treatment of HNSCC.
Citation Format: Dali Zheng, Weitao Chen, Youguang Lu. Epigenetic activated IL1B promotes tumor progression of tongue cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A54.
Abstract A56: Alteration of tumor metabolism by antitumor CD4+ T cells leads to tumor rejection
Authors: Zhou Gang , Habetesion Tsadik , Ding Zhi-Chun 
Published: June 2021

Abstract
Mounting evidence has revealed a dynamic metabolic crosstalk between cancer cells and T cells. It is evident that the metabolic constraints imposed by cancer cells compromise T-cell metabolic fitness and render T cells dysfunctional even in the face of antigenic stimulation. However, whether and how T cells affect tumor cell metabolism remains unclear. In the present study, we report that adoptive transfer of tumor-specific CD4+ T cells following CTX preconditioning gave rise to polyfunctional CD4+ effector cells capable of concomitantly producing multiple inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interferon gamma (IFNγ). These CD4+ effector cells induced profound metabolic changes in tumors before tumor regression was evident. Disruptions in multiple metabolic pathways converged to cause defective synthesis of the major cellular antioxidant glutathione (GSH), resulting in severe GSH deficiency, heightened reactive oxygen species (ROS) accumulation, and oxidative DNA damage in tumor cells. We demonstrated that tumor cell-intrinsic TNF-α signaling was required to synergize with chemotherapy to intensify ROS production in tumor via a mechanism involving nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidases. Our data provide new insight into the impact of an effective immunotherapy on tumor metabolism and identify tilting tumor redox toward excessive oxidative stress as an important mechanism underlying the efficacy of adoptive immunotherapy.
Citation Format: Gang Zhou, Tsadik Habetesion, Zhi-Chun Ding. Alteration of tumor metabolism by antitumor CD4+ T cells leads to tumor rejection [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A56.