bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-007: The emergence of tumor organoid engineering as a powerful tool for drug efficacy and mechanism of action profiling
Authors: Wang Fei , Zhou Rongyun , Dong Xinlong , Ma Yuqing , Zhou Jun , Xu Xiaoxi , Huang Yujun , Li Henry , Wang Phillip S-Z 
Published: September 2020

Abstract
Introduction: Patient-derived models such as organoids are a powerful translational tool for preclinical research with several advantages over current conventional models: 1) they are derived from stem cells with self-organizing and renewal properties reflecting the 3D structure and morphology of original tissue; 2) they preserve the original genomic, physiological, and multicellular identity thereby representing patient diversity and heterogeneity in a dish; 3) they provide in vitro convenience for greater throughput for screening large numbers of compounds and/or patients; 4) they are amenable to genetic engineering. Methods: We have used Hubrecht Organoid Technology (HUB) protocols to systematically create a biobank of organoids derived from a well-annotated patient-derived xenograft (PDX) library (the world's largest commercially available PDX library with over 2,500 models, covering a variety of carcinomas, with extensive pathology, genomic, and treatment information), referred to as PDX-derived organoids or PDXOs. Results: We have currently developed more than 200 PDXOs covering many cancer types, including colorectal, gastric, liver, lung, bladder, breast, ovarian, pancreatic cancer, etc. Genomic analyses have demonstrated that PDXOs largely preserve the histo- and molecular pathology of the original PDX. In vitro maintenance of PDX models as organoids enables genetic manipulation to be performed, which is not possible for in vivo PDX models, thereby creating new models to facilitate drug development. We have employed both lentivirus-based and CRISPR/Cas9-based approaches to modify various tumor organoid models with luciferase, tumor associated antigens (TAA), and some EGFR mutants unavailable in current preclinical model panels. These engineered organoid models, alongside corresponding in vivo matched models, have been incorporated into a new drug efficacy platform. Preliminary results show that these engineered organoid models greatly expand the capacity and application of our current organoid bank. Conclusions: In summary, engineered cancer organoids are a great tool to enrich and diversify current tumor organoid biobanks, particularly for unavailable and clinically relevant models to be used for drug testing, as well as for studies on mechanisms of action and drug resistance.
Citation Format: Fei Wang, Rongyun Zhou, Xinlong Dong, Yuqing Ma, Jun Zhou, Xiaoxi Xu, Yujun Huang, Henry Li, Phillip S-Z Wang. The emergence of tumor organoid engineering as a powerful tool for drug efficacy and mechanism of action profiling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-007.
Abstract LB-018: Chemotherapeutic stress influences epithelial-mesenchymal transition and stemness in cancer stem cells of triple-negative breast cancer
Authors: Li Xiao , Strietz Juliane , Bleilevens Andreas , Stickeler Elmar , Maurer Jochen 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen and progesterone receptors (ER, PR) and lacking an overexpression of human epidermal growth factor receptor 2 (HER2). Apart from this lack of therapeutic targets, TNBC also shows an increased capacity for early metastasis and therapy resistance. Currently, many TNBC patients receive neoadjuvant chemotherapy (NACT) upon detection of the disease. With TNBC likely being driven at least in part by a cancer stem-like cell type, we wanted to evaluate the response of primary cancer stem cells (CSCs) to standard chemotherapeutics. Therefore, we set up a survival model using primary CSCs to mimic tumor cells in patients under chemotherapy. Breast cancer stem cells (BCSCs) were exposed to chemotherapeutics with a sublethal dose for six days. Surviving cells were allowed to recover in culture medium without chemotherapeutics. Surviving and recovered cells were examined in regard to proliferation, migratory capacity, sphere forming capacity, epithelial-mesenchymal transition (EMT) factor expression at the mRNA level, and cancer-related microRNA (miRNA) profile. Our results indicate that chemotherapeutic stress enhanced sphere forming capacity of BCSCs, and changed cell morphology and EMT-related gene expression at the mRNA level, whereas the migratory capacity was unaffected. Six miRNAs were identified as potential regulators in this process.
Citation Format: Xiao Li, Juliane Strietz, Andreas Bleilevens, Elmar Stickeler, Jochen Maurer. Chemotherapeutic stress influences epithelial-mesenchymal transition and stemness in cancer stem cells of triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-018.
Abstract LB-020: The replication factor MCM10 maintains breast cancer stem-like cells that constitutively experience c-Myc-driven replication stress
Authors: Gotoh Noriko 
Published: September 2020

Abstract
Cancer stem-like cells (CSCs) are thought to be responsible for recurrence of tumors and poor prognosis due to their higher tumor-initiating capacity and resistance against chemotherapeutic agents, although the underlying mechanisms remain unclear. Here, we uncover a critical role of the replication factor mini-chromosome maintenance protein 10 (MCM10) in enabling breast cancer-derived CSCs to deal with constitutively accumulating DNA replication stress. Transcriptomic analysis of patient-derived breast cancer cells revealed that c-Myc downstream target genes and replication stress response genes were highly upregulated in CSC-enriched spheroid cells. Upregulated c-Myc enhanced the transcriptional activity especially at nucleoli, leading to DNA replication stress caused by collision of transcription and replication machineries. MCM10, one of the most upregulated factors in CSCs, showed important roles for enabling cells to survive under such condition through activating dormant origins. MCM10 depletion decreased tumorigenesis, tumor sphere-forming capacity, expression levels of stemness markers, and tumor-initiating capacity, suggesting that elevated MCM10 levels are vital for CSC survival and proliferation. On the other hand, overexpression of MCM10 helped cells to proliferate in medium containing hydroxyurea (HU), a chemotherapeutic agent that induces replication stress. We therefore conclude MCM10 plays critical roles for cancer cell proliferation under DNA replication stress, which is more pronounced in CSCs with upregulated c-Myc activity and in cells treated with chemotherapeutic agents, and propose to target MCM10 for therapy of both CSCs and other cancer cells.
Citation Format: Noriko Gotoh. The replication factor MCM10 maintains breast cancer stem-like cells that constitutively experience c-Myc-driven replication stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-020.
Abstract LB-055: Novel therapeutic option targeting the tumor cell lysosomes
Authors: Joncour Vadim Le , Filppu Pauliina , Holopainen Minna , Hyvönen Maija , Turunen S. Pauliina , Sihto Harri , Burghardt Isabel , Jääskeläinen Juha , Weller Michael , Lehti Kaisa , Käkela Reijo , Laakkonen Pirjo 
Published: September 2020

Abstract
Malignant brain tumors represent a surgical and therapeutic challenge. Despite major breakthrough in the precision neurosurgery and the personalized medicine, it remains impossible to circumvent the tumor relapse. This is due to the highly infiltrative nature of the glioma cells, with single tumor-initiating cells invading far distances in the brain. However, we recently identified a major flaw in the invasive tumor cell biology: a high sensitivity to the lysosomal membrane permeabilization (LMP). We first identified the fatty acid binding-protein 3 (FABP3) specifically expressed by invasive gliomas cells. Expression of FABP3 is indispensable to the transportation of poly-unsaturated fatty acids (PUFAs), which cannot be otherwise synthetized by the cells, from the extracellular space to biological membranes. Silencing of FABP3 stopped the supply of PUFAs that are essential to the lysosomal membrane maintenance. Induction of the LMP activated a cascade of events including the release of the lysosomal cathepsins in the cytosol, leading to the tumor cell death. Interestingly, the specific killing of invasive glioma cells through the LMP can be achieved by using lysosomotropic drugs, such as anti-histamines. These cationic amphiphilic molecules accumulate in the lysosome and induce the phospholipidosis of the lysosomal membrane. We therefore tested the ability of the blood-brain-barrier permeable clemastine, an anti-histamine, to reduce the tumorigenicity several patient-derived gliomas implanted in nude mice. Although clemastine treatment did not modify the primary tumor mass growth, it completely eradicated the invasive population. These promising results obtained by therapeutic activation of the LMP could also be beneficial for other aggressive cancers models, such as brain metastases of breast cancer or metastatic pancreatic cancer.
Citation Format: Vadim Le Joncour, Pauliina Filppu, Minna Holopainen, Maija Hyvönen, S. Pauliina Turunen, Harri Sihto, Isabel Burghardt, Juha Jääskeläinen, Michael Weller, Kaisa Lehti, Reijo Käkela, Pirjo Laakkonen. Novel therapeutic option targeting the tumor cell lysosomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-055.
Abstract LB-130: Suppression of tumor immune activity in adrenocortical carcinoma with excess glucocorticoid
Authors: Greenstein Andrew E. , Habra Mouhammed Amir , Mura Marzena , Biernat Paweł , Piatek Marek J. , Grauer Andreas , Shepherd Stacie Peacock 
Published: September 2020

Abstract
Introduction: Elevated glucocorticoid (GC) activity, while difficult to accurately quantify, has been implicated in the pathophysiology of multiple cancer types. Approximately half of adrenocortical carcinoma (ACC) patients exhibit excess GC (GC+), which provides a unique test case to assess correlates of GC activity. The broad immunosuppressive effects of GC may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. ACC multi-omics were analyzed to identify the molecular consequences of GC activity and assess the rationale for combining relacorilant, a glucocorticoid receptor (GR) antagonist, with an ICI in GC+ ACC.
Methods: GC status, mRNA expression, DNA mutation, and DNA methylation data from distinct adrenal resections (n=71) were accessed via The Cancer Genome Atlas (TCGA). To deconvolute immune cell type abundance, xCell was applied to the mRNA data. Random forest was used to derive gene signatures.
Results: The expression of 858 genes differed significantly between GC- and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of 7 pathways involved in steroid synthesis and secretion in GC+ cases. Nineteen pathways showed lower expression, most of which were related to natural killer cells, T-cells, and immune activity. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P=.003), CD8+ memory (P&lt;.001), and NKT-cells (P=.014) were depleted in GC+ cases, while tumor-associated neutrophils were enriched (P&lt;.001). Higher tumor mutation burden (TMB) was observed in the GC+ cases (P=.029). A gene signature predictive of GC status in ACC was derived and applied to other cancer types to identify tumors with GC+-like transcriptional profiles.
Conclusions: Reduced abundance of immune cells and immune-related transcripts in GC+ ACC provides insight into the mechanisms by which GC may limit response to ICI therapy. GR antagonism may increase immune related transcripts, thus promoting tumor immune response in GC+ ACC and other malignancies with elevated GC activity. This hypothesis will be tested in a Phase 1 trial of relacorilant + ICI.
Citation Format: Andrew E. Greenstein, Mouhammed Amir Habra, Marzena Mura, Paweł Biernat, Marek J. Piatek, Andreas Grauer, Stacie Peacock Shepherd. Suppression of tumor immune activity in adrenocortical carcinoma with excess glucocorticoid [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-130.
Abstract LB-131: Profile of glucose metabolism in bladder cancer patients and the inhibitory effect of sulforaphane on bladder cancer glycolysis by regulating microRNA expression
Authors: Shan Yujuan , Huang Lei 
Published: September 2020

Abstract
Object: We are committed to studying the characteristics of energy metabolism in bladder cancer patients, and to investigate the regulation of sulforaphane (SFN) on glucose metabolism in bladder cancer cells. Methods: Real-time PCR was used to detect the gene level of glycolysis key rate-limiting enzymes in bladder tumors, and para-carcinoma tissues as control. We also measured the activity of glycolysis enzymes in patient serum and bladder cancer cells by ELISA. Then we measured microRNAs level by microarray after SFN treatment. GO function and KEGG pathway enrichment analyses were used to gain insights into the biological roles and the potential pathway of different expression microRNAs. Results: Gene expression results showed that the level of PFK-1 was highly increased in tumor tissues. However, there is no significant differential in serum activity of PFK-1 as compared with control group. SFN obviously elevated microRNA expression related to glucose metabolism, including miR-200c, miR-34a and let-7. The activity of HK2, which can be blocked by miR-34a, was strongly inhibited in bladder cancer cells by incubating with 20 μmol/L SFN for 24 h. Furthermore, functional annotation analysis results suggest that miR-200c target genes were mainly enriched in 82 GO terms and 17 pathways (P &lt; 0.05), including mTOR signaling (p = 0.0154) and AMPK signaling (p = 0.0158), which also involved in the regulation of energy metabolism. Conclusion: Aberrant gene expression of PFK-1 is one of most important causes of glucose metabolic disorders in bladder cancer patients. SFN can significantly down-regulate glucose metabolism in bladder cancer cells by regulating the expression of glycolysis related-microRNAs.
Citation Format: Yujuan Shan, Lei Huang. Profile of glucose metabolism in bladder cancer patients and the inhibitory effect of sulforaphane on bladder cancer glycolysis by regulating microRNA expression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-131.
Abstract LB-163: Cost-effectiveness analysis of HBV-related hepatocellular carcinoma screening in cirrhosis patients with antiviral treatment in China
Authors: Zhang Meng , Li Yaoguang , Zhang Shunxiang , Zhang Jianying 
Published: September 2020

Abstract
Background/Aims: The majority of hepatocellular carcinoma (HCC) patients (&gt;80%)are attributable to hepatitis B virus (HBV) in China. Antiviral treatment is a public health strategy to slow down or change the progression of the disease so as to prevent HCC. In recent years, the Chinese government has been reducing the price of antiviral drugs responding to WHO program of global hepatitis B elimination. Therefore, we modelled the consequences of different screening strategies with or without antiviral treatment to evaluate the cost-effectiveness for HBV-related cirrhosis patients in China. Methods: We designed a markov model to compare no screening with 8 screening strategies in HBV-related cirrhosis patients aged 40 and older in China: annual/semiannual US, annual/semiannual US with AFP, annual/semiannual CT and annual/semiannual MRI. Meanwhile, to evaluate the cost-effectiveness of the strategies in the combination of screening and the antiviral treatment, we also assessed the other 8 screening strategies with antiviral treatment compared to the 8 non-antiviral strategies accordingly. Costs, quality-adjusted life-years (QALYs), life-years (LY) and incremental cost-effectiveness ratios (ICERs) were collected and used to assess the cost-effectiveness of screening strategies and antiviral therapeutics. Results: Semiannual CT strategy was less cost and more effective than no screening with 0.81 QALYs gained and $1092 saved. The ICER ($/QALY) for semiannual MRI strategy compared with semiannual CT strategy was $220,318 that was higher than the WTP ($29,331/QALY). As to antiviral treatment strategies, Semiannual CT strategy was also less cost and more effective than no screening with 0.48 QALYs gained and $535 saved. Not only was Semiannual CT the most efficacious strategy, but also the ICERs ($/QALY) were $4,681/QALY, $6,814/QALY and $11,560/QALY as the results by comparing annual US with AFP strategy, annual CT strategy and semiannual US with AFP strategy to semiannual CT strategy respectively. The QALY of semiannual CT with antiviral treatment increased by 5.37 compared to semiannual CT without antiviral treatment. The ICER was $3,944/QALY. Conclusions: Antiviral treatment appears to be a cost-effective strategy in HBV-related cirrhosis populations in China and semiannual CT with antiviral treatment strategy may be more cost-effective for HBV-related hepatocellular carcinoma Screening and prevention.
Citation Format: Meng Zhang, Yaoguang Li, Shunxiang Zhang, Jianying Zhang. Cost-effectiveness analysis of HBV-related hepatocellular carcinoma screening in cirrhosis patients with antiviral treatment in China [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-163.
Abstract LB-183: Sensitivity of cancer cells to oncolytic viruses is defined by IWS1 phosphorylation dependent epigenetic regulation of U2AF2 splicing and nucleocytoplasmic export of type I IFN transcripts
Authors: Laliotis Georgios I. , Kenney Adam D. , Orlacchio Arturo , Coppola Vincenzo , Yount Jacob S. , Tsichlis Philip N. 
Published: September 2020

Abstract
We have previously shown that phosphorylation of IWS1 by AKT (primarily AKT3) at Ser720/Thr721 promotes the binding of SETD2 to an Spt6/IWS1/Aly-Ref transcription elongation complex. This complex is bound via Spt6 to the Ser2-phosphorylated CTD of RNA Pol II. We have also shown that this results in the AKT-dependent trimethylation of Histone H3 at K36, a histone modification that contributes to the regulation of alternative splicing, and that this splicing pathway plays an important role in lung cancer. Here, we show that one of the genes targeted for alternative splicing via this mechanism is U2AF2, which encodes the splicing factor U2AF65. The predominant alternatively spliced U2AF2 transcript in cells which have lost IWS1, and in cells in which IWS1 is not phosphorylated, lacks exon 2, which encodes the SR domain of U2AF65. U2AF65 lacking the SR domain does not bind Prp19, a member of a seven-protein complex, which also contributes to RNA processing. U2AF65 and Prp19, along with the TREX complex, bind Cytoplasmic Accumulation Response Elements (CAR-E) in naturally intronless mRNAs and promotes their nucleocytoplasmic export. Examples of mRNAs whose transport is regulated by this mechanism include IFNα1, IFNβ1, HSPBP3 and c-Jun. Based on these data, we predicted that the production of type I IFNs would be dependent on IWS1 phosphorylation by AKT and that inhibition of this pathway would lead to increased sensitivity of cells to virus infection. Indeed, type I IFN production was decreased in such cells and infection with Vesicular Stomatitis Virus (VSV) was accordingly increased. In addition, whereas U2AF65 binds CAR-E elements in the RNA of type I interferons independent of IWS1 phosphorylation, the binding of Prp19 to the same RNA elements occured only in cells expressing AKT-phosphorylated IWS1. These data identify a mechanism by which AKT inhibits viral infection and suggest that inhibition of the AKT/IWS1 axis will increase the sensitivity of cancer cells to infection by oncolytic viruses.
Citation Format: Georgios I. Laliotis, Adam D. Kenney, Arturo Orlacchio, Vincenzo Coppola, Jacob S. Yount, Philip N. Tsichlis. Sensitivity of cancer cells to oncolytic viruses is defined by IWS1 phosphorylation dependent epigenetic regulation of U2AF2 splicing and nucleocytoplasmic export of type I IFN transcripts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-183.
Abstract LB-184: A lncRNA-histone acetyltransferase complex induces colorectal oncogenesis through regulation of a metabolic kinase network
Authors: Polytarchou Christos , Hatziapostolou Maria , Koutsioumpa Marina , Christodoulou Niki , Yau Tung On , Birli Eleni , Pomenya Odette , Montiel-Duarte Cristina , Joshi Swapna Mahurkar , Hommes Daniel W. , Verspaget Hein W. , Yu Jun , Iliopoulos Dimitrios 
Published: September 2020

Abstract
Long non-coding RNAs (LncRNAs) through interactions with other cellular macromolecules drive cell processes contributing to important cancer phenotypes. Here we show that HOTAIR, a highly up-regulated lncRNA in human colon cancers, induces transformation of human non-transformed colon epithelial cells. An exon 6 HOTAIR region directly binds the histone acetyltransferase PCAF (KAT2B). The HOTAIR/PCAF complex regulates H3K27 acetylation and transcriptional activation preferentially of genes encoding components of the PI3K/AKT/MEK pathways and induces cell metabolic reprogramming. The transcriptional signature of this HOTAIR/PCAF metabolic circuit is active in colon cancer and correlates with overall patient survival. Topological and mechanistic analyses were employed to characterize the HOTAIR/PCAF interface and design a reversible specific inhibitor (CPDI-1). Selective blocking of the HOTAIR-PCAF interaction, suppresses AKT activation and tumor growth. In conclusion, we demonstrate that disruption of a lncRNA-histone modifier complex interferes with the cancer epigenome and represents a novel approach for cancer therapeutics.
Citation Format: Christos Polytarchou, Maria Hatziapostolou, Marina Koutsioumpa, Niki Christodoulou, Tung On Yau, Eleni Birli, Odette Pomenya, Cristina Montiel-Duarte, Swapna Mahurkar Joshi, Daniel W. Hommes, Hein W. Verspaget, Jun Yu, Dimitrios Iliopoulos. A lncRNA-histone acetyltransferase complex induces colorectal oncogenesis through regulation of a metabolic kinase network [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-184.