bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A16: Characterization of ErbB family expression in intratibial bladder cancer xenografts: Considerations for preclinical modeling
Authors: Broses Luke J. , Day Kathleen C. , Udager Aaron M. , Day Mark L. 
Published: August 2020

Abstract
Background: Approximately 40% of patients with distant metastatic bladder cancer are diagnosed with bone metastases and a dismal 5-year survival rate of less than 10%. The bone has long been thought to act as “soil” for metastatic cells to “seed,” likely due to the favorable, albeit complex microenvironment that comprises various cell types and growth factors. A study by The Cancer Genome Atlas (TCGA) profiling 405 muscle-invasive bladder cancers reported alterations of the receptor tyrosine kinase pathway in 20% of these patients. This included amplification of EGFR in 9% of cases, mutation or amplification of ERBB2 in 9% of cases, and mutation of ERBB3 in 6% of cases. The purpose of this study was to correlate the expression of ErbB family members in human bladder cancer cell lines with their ability to grow as intratibial xenografts in immune-compromised mice.
Methods: We performed intratibial injections with six established human bladder cancer cell lines in 22 NSG mice and we allowed these xenografts to grow for five weeks. Four cell lines expressed luciferase and were measured for bioluminescent signals at multiple time points. The resulting formalin-fixed, paraffin-embedded tibiae were processed for immunohistochemistry (IHC) which utilized human specific antibodies to CK8, EGFR, HER2, Ki-67, and uroplakin.
Results: The four luciferase-expressing cell lines exhibited increasing bioluminescent signal over the duration of the study (n=14). Five cell lines had positive human anti-Ki-67 staining in the tibia, confirming their growth in the bone after the intratibial injection. All five cell lines maintained expression, and in certain cases overexpression, of EGFR and HER2 in the intratibial xenografts. We observed an 87.5% take rate (n=16) in a subset of bladder cell lines (5 out of 6) and only the UM-UC-12 cell line exhibiting a 0% take rate (n=6).
Conclusion: The high take rate of these five cell lines in the tibia exceeded that of previous studies (25-50%), indicating that the take rate is cell line dependent. Characterizing the ErbB expression profile of individual cell lines in the tibia xenograft model is an important consideration before using these xenografts as a preclinical model. Furthermore, ubiquitous expression of ErbB receptors in tibiae xenografts highlights the importance of growth factor signaling in metastatic bladder cancer and the potential for ErbB targeted therapy.
Citation Format: Luke J. Broses, Kathleen C. Day, Aaron M. Udager, Mark L. Day. Characterization of ErbB family expression in intratibial bladder cancer xenografts: Considerations for preclinical modeling [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A16.
Abstract A20: Disruption and restoration of pioneer transcription factor function in bladder cancer
Authors: Schuerger Caroline , Gu Xiaorong , Parker Yvonne , Lindner Daniel , Jha Babal 
Published: August 2020

Abstract
Urothelial bladder cancer (BLCA) is characterized by the failure to complete epithelial-differentiation. The mechanisms underlying this failure are unknown. To address this knowledge gap, we used unbiased analyzes to identify 1,000 genes significantly suppressed in BLCA vs normal bladder (p&lt;0.001, FDR&lt;0.01) (n=426, TCGA RNA-seq). Remarkably, these genes are located in compacted chromatin in embryonic stem cells (ESC) (decreased H3K4me3, increased CpG methylation), while 1,000 genes upregulated in BLCA vs normal bladder are located in open chromatin at this same ultimate baseline. This striking pattern in unbiased analyses suggested pioneer transcription factor (TF) loss of function in BLCA: pioneer TF access compacted chromatin to initiate the remodeling necessary for gene activation. The pioneer TF hub containing FOXA1, GATA4 is highly expressed in normal bladder, and these pioneer TFs are frequently haploinsufficient in BLCA, 32% and 56%, respectively. We pulled down endogenous FOXA1, the most expressed TF, from UM-UC-6 BLCA cells. Proteomic analyzes by mass spectrometry revealed enrichment for corepressors (DNMT1) over coactivators (ARID1A) in this pioneer TF hub. Genetic analyses showed frequent mutation/deletion of the coactivators: 43% bi-allelic ARID1A inactivation, while corepressors, e.g., CHD4 and DNMT1, were amplified or unaltered. Restoration of ARID1A into UM-UC-6 upregulated epithelial genes, downregulated MYC, upregulated CDKN1B, and terminated proliferation. To translate into therapy, we confirmed using immunoprecipitation LCMS/MS that DNMT1-depletion using noncytotoxic concentrations of the clinical drug decitabine (0.2-0.5 μM) shifted hub composition to coactivators, to thereby induce terminal epithelial-differentiation of BLCA cells. This was also seen in vivo in UM-UC-6 xenograft: very low dose non-cytotoxic decitabine (0.1 mg/kg) combined with an inhibitor of its degradation, THU, decreased tumor size more than standard high-dose cytotoxic gemcitabine/cisplatinum. Thus, BLCA suppresses hundreds of epithelial-differentiation genes via corepressor/coactivator imbalance in the bladder pioneer TF hub. Sensitivity of the pioneer TF hub to corepressor/coactivator stoichiometry, however, also enables pharmacologic reduction of corepressors to compensate for genetic reduction of coactivators, to thereby release BLCA cells to destined terminal epithelial fates.
Citation Format: Caroline Schuerger, Xiaorong Gu, Yvonne Parker, Daniel Lindner, Babal Jha. Disruption and restoration of pioneer transcription factor function in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A20.
Abstract A27: Fidelity of a PDX-CR model for bladder cancer
Authors: Mondal Abdul M. , Ma Ai-Hong , Li Guangzhao , Krawczyk Ewa , Jie Lu , Schlegel Richard , Pan Chong-Xian , Liu Xuefeng 
Published: August 2020

Abstract
Current efforts for cancer drug discovery have predominantly been deterred by the lack of appropriate preclinical cancer models that recapitulate the characteristics of this complex disease. Patient-derived xenografts (PDXs) are widely recognized as a more physiologically relevant preclinical model than organoids and standard cell lines, and often resemble the original tumor histology, genetic profile, and gene-expression patterns. Despite these benefits, PDX models are limited by their variable engraftment rate, lack of sustained growth in vitro, low throughput for drug screening, lower amenability to experimental manipulation, and high cost. In this study, we utilized conditional reprogramming (CR) technology to generate four CR cell (CRC) lines from bladder cancer PDXs. The CR cells were then employed to evaluate the genetic status and drug sensitivity and compared with the parental PDX tumors. All the established CRC lines maintained parental mutations and allele frequencies without clonal drift. Moreover, the drug responses of the parental PDX tumors in vivo were retained in the established CRC lines in vitro. Altogether, CR technology offers the ability to generate cell lines and expand PDX cells without compromising fundamental biologic properties of the model, thereby allowing for in vitro use to reduce animal usage, variability, and study cost. Perhaps more importantly, the CR cell lines established here can be used for personalized high-throughput drug screening as well as for studying drug-resistance mechanisms.
Citation Format: Abdul M. Mondal, Ai-Hong Ma, Guangzhao Li, Ewa Krawczyk, Lu Jie, Richard Schlegel, Chong-Xian Pan, Xuefeng Liu. Fidelity of a PDX-CR model for bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A27.
Abstract B08: MSH2 downregulation induces chemoresistance in bladder cancer
Authors: Goodspeed Andrew E. , Jean Annie , Costello James C. 
Published: August 2020

Abstract
Treatment of muscle-invasive bladder cancer has seen little improvement in three decades. The objective of this study is to identify genes and pathways that associate with cisplatin resistance in bladder cancer. A whole-genome, CRISPR-based screen was performed in the MGHU4 bladder cancer cell line treated with cisplatin to identify genes that mediate resistance to cisplatin. Targeted validation was performed in vitro in another bladder cancer cell line, 253J. MSH2 and MLH1 are prominent components of the mismatch repair. These are the top two genes that have the largest effect on cisplatin resistance according to our synthetic lethal screen. Bladder cancer cells with an MSH2 knockdown are resistant to cisplatin in vitro, in part due to a reduction in apoptosis. MSH2 was also investigated in a publicly available bladder cancer dataset containing 340 bladder cancer patients with treatment, protein, and survival information. Bladder cancer patients with low protein levels of MSH2 have poorer overall survival when treated with cisplatin- or carboplatin-based therapy. If confirmed in follow-up studies, MSH2 protein level may serve as a prospective biomarker of chemotherapy response in this cancer type.
Note: This abstract was not presented at the conference.
Citation Format: Andrew E. Goodspeed, Annie Jean, James C. Costello. MSH2 downregulation induces chemoresistance in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B08.
Abstract B12: Acetate metabolism mediated by acetyl-CoA synthetase 2 in cisplatin-resistant bladder cancer
Authors: Wen He , Lee Sujin , Zhu Wei-Guo , Lee Ok-Jun , Yun Seok Joong , Kim Jayoung , Park Sunghyouk 
Published: August 2020

Abstract
Introduction and Objective: Cisplatin is an important chemotherapeutic agent against metastatic bladder cancer, but resistance often limits its usage. With the recent recognition of lipid metabolic alterations in bladder cancers, we studied the metabolic implications of cisplatin resistance using cisplatin-sensitive (T24S) and -resistant (T24R) bladder cancer cells.
Methods: To test whether there should be differences in metabolism and metabolism-associated pathways between cisplatin-sensitive and resistant bladder cancer cells, we applied the live metabolomics approach that we recently developed to isogenic bladder cancer cell lines T24S (cisplatin sensitive) and T24R (cisplatin resistant). The metabolites generated from 13C-glucose tracer were monitored with 2D 1H-13C HSQC NMR in real time.
Results: Real-time live metabolomics revealed that T24R cells consume more glucose, leading to higher production of glucose-derived acetate and fatty acids. Along with the activation of general metabolic regulators, enzymes involved in acetate usage (ACSS2) and fatty acid synthesis (ACC) and a precursor for fatty acid synthesis (acetyl-CoA) were elevated in T24R cells. Consistently, metabolic analysis with 13C isotope revealed that T24R cells preferred glucose to acetate as the exogenous carbon source for the increased fatty acid synthesis, contrary to T24S cells. In addition, ACSS2, rather than the well-established ACLY, was the key enzyme that supplies acetyl-CoA in T24R cells through glucose-derived endogenous acetate. The relevance of ACSS2 in cisplatin resistance was further confirmed by the abrogation of resistance by an ACSS2 inhibitor and, finally, by the higher expression of ACSS2 in the patient tissues with cisplatin resistance.
Conclusions: Our results may help improve the treatment options for chemoresistant bladder cancer patients and provide possible vulnerability targets to overcome the resistance.
Citation Format: He Wen, Sujin Lee, Wei-Guo Zhu, Ok-Jun Lee, Seok Joong Yun, Jayoung Kim, Sunghyouk Park. Acetate metabolism mediated by acetyl-CoA synthetase 2 in cisplatin-resistant bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B12.
Abstract B14: Epigenetic remodeling of cancer metabolisms in cisplatin-resistant bladder cancer
Authors: Yeon Austin , You Sungyong , Kim Minhyung , Gupta Amit , Park Myung Hee , Weisenberger Daniel , Liang Gangning , Kim Jayoung 
Published: August 2020

Abstract
Introduction and Objective: Alterations in DNA methylation are important epigenetic markers in bladder cancer (BC). These epigenome modifications drive the mechanisms of aggressive chemoresistant BC. Clinicopathologic biomarkers that indicate chemotherapeutic resistance are critical for better assessing treatment strategies for individual patients. Thus, in this study, we aimed to determine whether DNA methylation of certain metabolic enzymes is significantly altered in cisplatin-resistant BC cells.
Methods: To characterize CpG methylation and nucleosome accessibility in cisplatin-resistant BC cells, the Illumina Infinium HM450 DNA methylation assay was performed. Perturbed gene expression was found to be associated with cisplatin resistance, and the biologic roles of spermidine/spermine N1-acetyltransferase (SAT1) and argininosuccinate synthase 1 (ASS1) were further studied using qRT-PCR analysis and various cell biology assays, including Western blot.
Results: ASS1 and SAT1, genes for amino acid and polyamine metabolism catalysts, respectively, were found to be vastly hypermethylated, resulting in greatly downregulated expression. ASS1 expression is of particular interest because prior studies have demonstrated its potential association with BC stage and recurrence. In regard to chemoresistance, we found that aberrant expression or induced stimulation of SAT1 restored cisplatin sensitivity in the cell culture system. We also found that the addition of exogenous arginine deiminase through administration of ADI-PEG 20 (pegylated arginine deiminase) increased ASS1 expression and enhanced cisplatin's apoptotic effects.
Conclusions: Our study demonstrates a novel mechanistic link between the epigenetic perturbation of SAT1 and ASS1 and cancer metabolism in cisplatin-resistant bladder cancer cells. These findings suggest potential utility of SAT1 and ASS1 as predictive biomarkers in resensitizing bladder cancer to chemotherapy and personalizing therapy.
Citation Format: Austin Yeon, Sungyong You, Minhyung Kim, Amit Gupta, Myung Hee Park, Daniel Weisenberger, Gangning Liang, Jayoung Kim. Epigenetic remodeling of cancer metabolisms in cisplatin-resistant bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B14.
Abstract B20: Characterization of tumor mutational landscape in smokers and nonsmokers with urothelial carcinoma
Authors: Walasek Aleksandra , Almassi Nima , Teo Min Yuen , Funt Samuel , Schultz Nikolaus , Dalbagni Guido , Hu Wenhu , Al-Ahmadie Hikmat , Bajorin Dean F , Rosenberg Jonathan E , Iyer Gopakumar , Bochner Bernard H. , Solit David B. , Pietzak Eugene J. 
Published: August 2020

Abstract
Introduction and Objectives: Smoking is a major risk factor for development of bladder cancer. It has been previously shown that smoking-related and non-smoking-related cancers have characteristic mutational signatures. Hypothesizing that somatic alterations differ between smokers and nonsmokers with urothelial carcinoma, we used next-generation sequencing to evaluate for differences in genomic alterations between these two groups of patients.
Methods: We identified in our prospectively maintained institutional database all patients with urothelial carcinoma whose tumors underwent next-generation sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. A panel of genes previously reported by The Cancer Genome Atlas (TCGA) as being commonly mutated in bladder cancer was chosen for analysis.
Results: A total of 1,044 samples from 968 patients were included in the analysis. Seven hundred eighty-five (85%) of the samples represented bladder tumors and 259 (25%) of the samples represented tumors of the upper tract. Patients with smoking history comprised 66% of the cohort. The most frequently altered genes in active or former smokers and never smokers were TERT promoter (55% and 60%), TP53 (43% and 41%), KDM6A (30% and 26%), and FGFR3 (27% and 26%).
Conclusions: Mutational profiling of urothelial tumors in this large cohort of patients showed high incidence of genomic alterations consistent with prior studies. The frequency of alterations in these genes was similar between smokers and nonsmokers. To further understand smoking-related mutational process, we are examining mutational signatures and differences in genomic alterations as a function of smoking intensity exposure.
Citation Format: Aleksandra Walasek, Nima Almassi, Min Yuen Teo, Samuel Funt, Nikolaus Schultz, Guido Dalbagni, Wenhu Hu, Hikmat Al-Ahmadie, Dean F Bajorin, Jonathan E Rosenberg, Gopakumar Iyer, Bernard H. Bochner, David B. Solit, Eugene J. Pietzak. Characterization of tumor mutational landscape in smokers and nonsmokers with urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B20.
Abstract B30: A living biomarker from urine to predict drug efficacy and recurrence of bladder cancer
Authors: Liu Xuefeng 
Published: August 2020

Abstract
The culture of cancer cells from urine samples is a simple, noninvasive technique that has the potential to advance the diagnosis, treatment, and monitoring of patients with bladder cancer, and the generation of such urine-derived cultures can provide both genetic and phenotypic data for precision medicine. In this study we collected urine and/or tumor biopsies from 23 bladder cancer patients and used conditional reprogramming (CR) to generate cell cultures from each of these sources. Using this CR technique, the overall success rate of culturing primary bladder cancer cells from the urine of bladder cancer patients was 96% (22/23), with 100% (18/18) of high-grade bladder cancers and 80% (4/5) of low-grade cancers generating cultures. No CR cultures (0/7) were generated from the urine of cancer-free participants. We characterized CR cells at cellular and genetic levels. The therapeutic responses of urine CRCs and tumor CRCs were also distinguishable from different patients and displayed similar patterns if derived from the same patient. This rapid, efficient, and noninvasive method for generating cultures of bladder cancer cells can be used potentially for high-throughput drug screening, predicting patient clinical responses, and monitoring tumor initiation and recurrence.
Citation Format: Xuefeng Liu. A living biomarker from urine to predict drug efficacy and recurrence of bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B30.
Abstract IA01: The epigenetics of cancer
Authors: Jones Peter A. 
Published: August 2020

Abstract
Human cancers are initiated and maintained by DNA mutations and also by alterations in the cancer epigenome. The interaction between these processes is underscored by the observation that all human cancers contain DNA methylation aberrations and also frequently harbor mutations in genes that modify the epigenome. These include the enzymes that apply and remove methyl groups to and from cytosine, DNMT3A and TET2. Abnormal DNA cytosine methylation has received the most attention in our understanding of its potential to silence tumor suppressor genes and thus to directly contribute to the malignant phenotype. There are now many drugs that can target the epigenome, and I will focus on those that inhibit DNA methylation. It is important that we understand how these drugs elicit responses in patients, and most of the attention to date has centered on their ability to activate genes that are methylated and altered in a cancer relative to the normal tissue. However, a large percentage of the human genome codes for transposable elements, and these are often silenced by DNA methylation. Activation of these transposable elements can give rise to a state of “viral mimicry” in which a cancer cell behaves as though it is infected by an exogenous virus. I will explore how this activation of transposable elements may contribute to an interferon response that leads to apoptosis of cancer cells and to increased visibility to the immune system. Coupling epigenetic therapies with other approaches may be useful in the future in the treatment of cancers, including bladder cancer.
Citation Format: Peter A. Jones. The epigenetics of cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA01.