bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 101: Pentraxin-3 exacerbates glioblastoma invasion and angiogenesis through IL8-VEGF signaling in tumor microenvironment: PTX3 is a potential target for GBM suppression
Authors: Wesley Umadevi V. , Clark Paul , Sutton Ian , Kuo John , Dempsey Robert 
Published: August 2019

Abstract
Background: Glioblastoma (GBM) is highly invasive and resistant to multimodal treatment due to distorted vasculature and aggravated inflammation in a tumor microenvironment rich in dysregulated cytokines and growth factors. This phenomenon is partly attributed to GBM stem cells (GSC) that release angiogenic and inflammatory cytokines. The glycoprotein pentraxin-3 (PTX3), a modulator of inflammation, is correlated with disease severity in some cancers. However, its role in GBM and the molecular mechanisms of PTX3-mediated oncogenesis remain unclear. In this study, we examined the role of PTX3 in GBM growth and invasion, using in vitro and in vivo models.
Methods: Patient derived GSC lines were isolated and validated. Tumor tissue micro arrays (TMA) were used to determine the association of PTX3 expression with patient GBM specimens representing various degree of disease. Intracranial tumor xenograft/orthotopic mouse models, cell culture models, proteomic profiling, immunohistochemistry, molecular and biochemical approaches were used.
Results: Proteomic profiling identified increased PTX3 expression in GSCs as compared to GBM lines, and correlated with the degree of GSC invasiveness in an orthotopic tumor xenograft model. Increased PTX3 correlated with cell cycle progression and survival under hypoxic micro-environment. Conditioned media obtained from PTX3-over-expressing U87 cell line enhanced pro-angiogenic tube formation from endothelial cells. TMA screening showed that PTX3 expression is substantially increased in more than 70% of GBM specimans. Furthermore, PTX3 over-expression significantly increased survival of U87 cells under hypoxic conditions and resulted in increased tumor growth and invasion in an intracranial tumor xenograft mouse model. Upregulation of PTX3 in these tumors was associated with increased levels of inflammatory and angiogenic markers including interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), but decreased levels of thrombospondin1, a major anti-angiogenic factor. Downstream activation of PI3K/Akt - NFkB signaling pathways was also observed.
Conclusion: PTX3 is dysregulated in GBM, and may augment inflammation and angiogenesis in tumor microenvironment. Thus, PTX3 may serve as an inflammatory marker for GBM microenvironment and also may represent a potential therapeutic target for GBM suppresion.
Citation Format: Umadevi V. Wesley, Paul Clark, Ian Sutton, John Kuo, Robert Dempsey. Pentraxin-3 exacerbates glioblastoma invasion and angiogenesis through IL8-VEGF signaling in tumor microenvironment: PTX3 is a potential target for GBM suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 101.
Abstract 1020: p300 and CBP targeting in castration therapy resistant prostate cancer
Authors: Furlan Tobias , Sampson Natalie , Santer Frédéric R. , Culig Zoran 
Published: August 2019

Abstract
p300 and CBP interact with transcription factors and other proteins via their histone acetyltransferase domain (HAT) and a bromodomain (Bd). In prostate cancer, p300 and CBP act as oncogenes and are commonly upregulated. p300 and CBP are valid targets for therapy due to their function as androgen receptor (AR) coactivators and involvement in castration resistance. Revealing downstream pathways and their function in cancer cell proliferation and resistance should further identify potential novel therapeutic targets. The effect of the p300/CBP HAT inhibitor C646 and the Bd inhibitor ICBP-112 on viability was tested. To this end several human PCa cell lines with different AR expression levels and resistance status were used. The resistant cells were derived from DUCaP, LAPC4 and LNCaP cells chronically treated with Enzalutamide (DUCaP ENZA, LAPC4 ENZA and LNCaP ABL ENZA). Resistance was verified by viability assay. Regulation of AR downstream targets was studied by qRT-PCR and Western blot. Gene expression in the different DUCaP and LNCaP sublines after inhibitor treatment was analyzed with RNAseq. Both inhibitors exhibited IC50 values on viability at micromolar concentrations with a significantly lesser effect on androgen-insensitive PC3 cells compared to AR sensitive cells. Significantly increased sensitivity to inhibitors was observed in enzalutamide-resistant DUCaP ENZA, LAPC4 ENZA and LNCaP ABL ENZA cell lines relative to parental cells: respectively 1.83- (*), 2- (*) and 2.7-fold (*) for C646 and not significant, 1.8- (p&lt;0.1) and 1.56-fold (*) for ICBP-112. Moreover, ICBP-112 treatment of DUCaP cells significantly reduced expression of the AR target genes FKBP5, PSA and TMPRSS2 0.6- (**), 0.57- (**) and 0.37-fold (***) respectively. Similar results were obtained with DUCaP ENZA cells 0.46- (*), 0.45- (*) and 0.57-fold (ns) for FKBP5, PSA and TMPRSS2, respectively. Whilst less pronounced, this regulation was also observed at the protein level. Similar results were obtained with C646. RNAseq results suggest multiple changes in sublines after chronic enzalutamide treatment in DUCaP and LNCaP cells. Inhibition of p300 and CBP reduced androgen-, myc- and parts of an EMT-signature, which are likely involved in the development of enzalutamide resistance. Taken together, C646 and ICBP-112 are effective inhibitors of AR dependent PCa. Furthermore, differences between cell lines suggest that the AR background and other factors influence the inhibitor effectivity. A significantly increased effect of the HAT and Bd inhibitors in CRPC suggests an important role for p300/CBP in CRPC.
Citation Format: Tobias Furlan, Natalie Sampson, Frédéric R. Santer, Zoran Culig. p300 and CBP targeting in castration therapy resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1020.
Abstract 1022: The role of dopamine signaling in prostate cancer disparities
Authors: Pickett Isaiah R. , Boston Ava M. , Almathkour Marwah M. , Ragin Camille , Bilen Mehmet A. , Osunkoya Adeboye O. , Cinar Bekir 
Published: August 2019

Abstract
Prostate cancer is the second leading cause of cancer-related deaths among men in western countries. Majority of prostate tumors often evolves as metastatic castration-resistant prostate cancer (CRPC) following hormonal therapy. Metastatic prostate cancer is the major cause of mortalities from this disease. African-American (AA) men have the highest incidence and mortality rate compared to any other race such as Caucasian American (CA). Despite recent advances, the cellular and molecular mechanisms that contribute to this disparity are unknown, obstructing the development of an effective therapy for this disease. Genetic and epigenetic studies have indicated that the biology of prostate cancer in AA men is substantially different from CA. Here, we investigate the dopamine (DA) signaling to better understand the mechanism of prostate cancer disparity. Our analysis of the prostate cancer public data sets showed that the dopamine receptor (DR) genes were amplified in up to 18% prostate cancer clinical cases. We have demonstrated that the levels of DR transcripts were significantly higher in the metastatic prostate cancer cell lines with African genetic ancestry than CA counters. We also demonstrate that the efficacy of pimozide, a potent DRD inhibitor and an FDA-approved antipsychotic, on AA cells was significantly higher than CA cells. In addition, we have found that L-dopa, an immediate precursor of DA differentially regulates the growth of AA and CA prostate cancer cells in a dose dependent manner. We also found that carbidopa, a potent inhibitor of the dopa decarboxylase, suppressed prostate cancer cell growth by L-dopa and showed that carbidopa re-sensitized CRPC cell line to enzalutamide, a potent inhibitor of androgen receptor (AR) signaling. These observations suggest that DA/DR signaling plays a critical role in prostate cancer disparity, making the DA/DR-AR axis a viable therapeutic target to reduce disparities in cancer mortality.
Citation Format: Isaiah R. Pickett, Ava M. Boston, Marwah M. Almathkour, Camille Ragin, Mehmet A. Bilen, Adeboye O. Osunkoya, Bekir Cinar. The role of dopamine signaling in prostate cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1022.
Abstract 1026: Oncogenic alterations in FGFR3 and ERBB2 lead to ligand-independent activation of PPARG in bladder cancer
Authors: Goldstein Jonathan T. , Berger Ashton C. , Strathdee Craig A. , Meyerson Matthew 
Published: August 2019

Abstract
PPARG is genomically activated in muscle-invasive bladder cancer through focal PPARG gene amplification and hotspot mutations in its heterodimer partner, RXRA. However, more than half of the PPARG-activated bladder tumors and cell lines do not have identifiable somatic alterations in either PPARG or RXRA. Using a PPARG-driven reporter assay in RT112 bladder cancer cell line, we screened probe compounds to identify candidate drivers of ligand-independent PPARG activation. We found that pan-FGFR inhibitors and MEK1/2 inhibitors antagonized the PPARG-driven reporter assay with potency similar to reported values for their cognate targets (1-20 nM) and interestingly, RT112 cells carry an FGFR3-TACC3 oncogenic fusion. In addition to the expected effects of these inhibitors on phospho-MEK1/2 and phospho-ERK1/2, they also inhibited production of canonical PPARG targets, including FABP4. In a second subset of cell lines, a parallel story was also observed for the effects of ERBB2 inhibitors in ERBB2 hotspot mutant bladder cancer. Taken together, these data uncover additional mechanisms for functional activation of PPARG in bladder cancer, suggest potential resistance mechanisms for FGFR and ERBB2 inhibitors, and provide a rationale for therapeutic combinations of PPARG modulators.
Citation Format: Jonathan T. Goldstein, Ashton C. Berger, Craig A. Strathdee, Matthew Meyerson. Oncogenic alterations in FGFR3 and ERBB2 lead to ligand-independent activation of PPARG in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1026.
Abstract 1035: PLEK2 promotes epithelial mesenchymal transition through increasing Snail1 in lung cancer cells
Authors: Liu En-Chu , Lee Tsai-Tu , Wu Shey-Lin , Lee Tai-Lin , Tsai Meng-Feng 
Published: August 2019

Abstract
Pleckstrin 2 (PLEK2), one of the pleckstrin homology domain proteins, have been suggested to modulate actin rearrangement and cell spreading in T lymphocytes. Recently studies also implicated that PLEK2 paly an importance role in human myeloproliferative neoplasms, melanoma, and lung cancers. PLEK2 mRNA genes were related to poor overall survival in lung adenocarcinoma patients. However, the biological functions of PLEK2 in lung cancer is not clear. We detected the expression of PLEK2 in various lung adenocarcinoma cell lines using quantitative RT-PCR methods. Molecular manipulations were performed to investigate the roles of PLEK2 in lung cancer cells. Over-expression of PLEK2 in lung cancer cells exhibited markedly promoting in the proliferation and anchorage independent growth, whereas reduced of PLEK2 was found to suppress lung cancer cell progression. This studies also indicated that PLEK2 may play an important role in the epithelial-mesenchymal transition (EMT) features, including a morphological change, increased invasive and migratory ability, reduction the epithelial marker expression and up-regulated EMT regulators. Our results suggested that PLEK2 expression induce lung cancer cell EMT phenomenon through up-regulation Snail1 expression. These results will provide information and help us to understand the roles of PLEK2 in lung cancer cells.
Citation Format: En-Chu Liu, Tsai-Tu Lee, Shey-Lin Wu, Tai-Lin Lee, Meng-Feng Tsai. PLEK2 promotes epithelial mesenchymal transition through increasing Snail1 in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1035.
Abstract 1042: Cellular plasticity and migratory modalities in high-grade serous ovarian carcinoma
Authors: Bapat Sharmila A. , Varankar Sagar 
Published: August 2019

Abstract
Epithelial-mesenchymal (E-M) switch associated plasticity is crucial for the gradual destabilization of tumor tissue architecture to facilitate metastasis. Several studies towards comprehension of the metastatic cascade employ an overview of the phenotype specific markers and their association with distinct functionalities of migration, invasion, stemness, anoikis resistance, ECM remodeling, etc. Recent work on the dissection of phenotypic transitions has identified the existence of transitionary intermediate states across multiple cancers which exhibit greater plasticity as compared to the two phenotypic extremes. In a previous study from our group, we successfully identified molecular subclasses in high grade serous ovarian carcinoma (HGSC) that were associated with distinct modes of metastatic dissemination viz., collective cell migration (CCM) and EMT. Towards, elucidating contributions of distinct phenotypic states to CCM and EMT along with a comprehension of associated molecular regulators we resolved a phenotypic spectrum along the E-M axis. Identification of five phenotypic states followed by their functional characterization was associated with differential migratory capabilities that were further dissected with the aid of live cell imaging to quantitatively distinguish CCM and EMT. Enhanced visual output and extraction of three quantitative metrics viz., displacement, velocity and nearest neighbours generated an informative tool for assessing migratory modes in vitro. Furthermore, these metrics identified migratory modalities inclusive of wound closure by proliferation (passive CCM), sheet-like cell migration (active CCM) and individual cell migration (EMT). Interestingly, phenotypic status and migratory modes across the spectrum emerged as a consequence of a balance between expression and differential sub-cellular localization of two transcription factors viz. Tcf21 and Slug. Application of the novel migratory analyses in view of chemotherapeutic challenges identified the emergence of an epithelial state across the spectrum facilitated by Tcf21 mediated Slug repression and resulted in a switch from EMT to aCCM-mediated migration. Our study thus provides a comprehensive dissection of the E-M axis in HGSC in view of associated functional attributes.
Acknowledgements: DBT Indo-Finnish Collaborative Grants, DBT Indo-Australia Collaborative Grants and NCCS Intramural Grants to SAB funded this research. SSV received fellowship from CSIR.
Citation Format: Sharmila A. Bapat, Sagar Varankar. Cellular plasticity and migratory modalities in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1042.
Abstract 1045: CRISPR/cas9 mediated generation of an EMT reporter cell line for metastatic breast cancer drug discovery and development
Authors: Enuameh Metewo S. , Shu Weiguo , Newman Robert 
Published: August 2019

Abstract
Among women, breast cancer continues to be the most common cancer, with metastasis being the leading cause of mortality in cancer patients around the world (DIZON et al. 2016). Epithelial to mesenchymal transition (EMT) - the process by which epithelial cells shift to the mesenchymal state, has been implicated in many aspects of breast cancer tumorigenesis, metastasis and drug resistance ). The accumulation of a large body of data on the association of EMT with cancer over the years has not resulted in EMT being an active target for therapeutic development. This is due in part to the lack of appropriate in vitro models. Here we have exploited some of the basic biology of EMT, to create an advanced in vitro metastatic breast cancer reporter cell line model for use in both basic research and discovery of new EMT inhibitors.
During EMT, E-cadherin protein expression is down regulated in cancer cells in association with the loss of cell-to-cell adhesion, apico-basal polarity and a change to a spindle-shaped morphology. By installing an emerald green fluorescent protein (EmGFP) tag on the C-terminus of the e-cadherin (ECAD) gene in the epithelial BT-474 breast cancer cell line via CRISPR/Cas9 genome editing, end-point or real-time EMT status of cells can be tracked under defined conditions. The EMT reporter cell line was verified at the nucleic acid (genomic and mRNA) and protein levels as well as in cell-based assays. Bio-functional evaluation of the BT-474 ECAD EmGFP cell line, shows that it responds to EMT induction. The subsequent EMT status of cells can be monitored in real time by observing and measuring ECAD EmGFP expression, in addition, the resulting mesenchymal cells have increased invasive capacities. Furthermore, this EMT reporter cell line shows sensitivity to the MEK1/2 inhibitor U0126 - thereby providing the basis for the use of this cell line in high-throughput screening (HTS) applications including the identification of new anti-EMT drugs for metastatic breast cancer. The BT-474 ECAD EmGFP reporter cell line is also a convenient and sensitive model for basic science research on the mechanisms of metastasis.
References
DIZON, D. S., L. KRILOV, E. COHEN, T. GANGADHAR, P. A. GANZ et al., 2016 Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol 34: 987-1011.
HAY, E. D., 1995 An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154: 8-20.
Citation Format: Metewo S. Enuameh, Weiguo Shu, Robert Newman. CRISPR/cas9 mediated generation of an EMT reporter cell line for metastatic breast cancer drug discovery and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1045.
Abstract 1048: CD44 promotes epithelial-mesenchymal transition (EMT) by regulating snail, ZEB1, and Caveolin-1 expression and predicts poor survival of ovarian cancer
Authors: Zhou Jiayi , Du Yan , Luan Baoxin , Yu Yinhua , Zhao Hongbo 
Published: August 2019

Abstract
CD44 is a stem cell marker which is involved in the generation of a stem cell niche and maintaining stem cell quiescence. Our data first demonstrated that CD44 knockdown by small silencing RNA abrogated both basal Snail expression and TGF-β1 induced Snail expression in HOPM and HOPM-snail cells. In addition, CD44 knockdown caused an decrease in ZEB1 expression. Further, RPPA data indicated that Caveolin-1 may be another regulative target of CD44, and western blotting analysis confirmed that CD44 knockdown caused an increase in Caveolin-1 expression. However, there was no obvious reciprocal regulation among ZEB1, Caveolin-1, and snail. Moreover, CD44 knockdown caused a decrease in cell migration, cell invasion and clone formation of HOPM and HOPM-snail cells.
We next observed the role of CD44 expression in the prognosis of ovarian cancer. Over-expression of CD44 was associated with advanced FIGO stage (P&lt;0.05). Univariate analysis result showed that histological subtype, FIGO stage, intravascular tumor thrombus, CA125 and CD44 expression were associated with overall survival and disease-free survival of ovarian cancer patients. Multivariate analysis showed that CD44 expression was an independent prognostic factor to predict both overall survival and disease-free survival of ovarian cancer patients. Taken together, our data showed that CD44 may be crucial for EMT process by regulating Snail, ZEB1, and Caveolin-1 expression. And CD44 is a potential prognostic factor as well as a treatment target for ovarian cancer.
Citation Format: Jiayi Zhou, Yan Du, Baoxin Luan, Yinhua Yu, Hongbo Zhao. CD44 promotes epithelial-mesenchymal transition (EMT) by regulating snail, ZEB1, and Caveolin-1 expression and predicts poor survival of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1048.
Abstract 1054: Systematic establishment of robustness and standards in xenograft experiments and analysis
Authors:   The NCI PDXNet Consortium, Evrard Yvonne , Chuang Jeffrey H. 
Published: August 2019

Abstract
Patient-Derived Xenograft (PDX) models are a valuable model system for demonstrating clinical translatability in the preclinical testing of therapeutic agents. Large PDX collections such as the NCI PDXNet Consortium are a critical resource for assays of therapeutic efficacy. However, research groups vary in their procedures for experiments and assessments, limiting conclusions about the robustness of PDX results and their mapping to patient outcomes. To determine the sensitivity of PDX assays to different procedures, the PDXNet conducted a study of temozolomide drug response for PDX models derived from three patients, performed in replicate across four PDX Development and Trial Centers (PDTCs) with all sites blinded to the procedures and results of other groups. The three PDX models were chosen based on prior treatment experiments conducted by the NCI Patient Derived Models Repository that showed that one model was sensitive, one was resistant, and one had intermediate sensitivity. Each PDTC used their internally developed SOPs, which varied in their procedures for establishment of xenografts, treatment dosing and scheduling, time period of study, and response criteria. Additionally all groups followed internal sequencing procedures to generate one exome-seq and one RNA-seq per model. Drug responses were consistent across all five testing groups, with each group identically classifying the sensitive, resistant, and intermediate models. We also trained novel statistical classifiers for assessing sensitivity, resistance, and intermediate response on 105 retrospective cohorts of mice collected among the PDTCs. In addition, we compared and benchmarked exome-seq and RNA-seq analysis pipelines developed by each individual PDTC on synthetic test data. We assessed the robustness of sequencing assessement on PDX tumors by applying the optimized pipeline across the replicate samples generated across the separate PDTC groups. Overall, our results show that drug responses of PDX models are consistent and robust across different academic centers. We are developing standardized SOPs for experimental procedures, response measurement, statistical assessment of response, and sequence analysis based on these results. All SOPs will be released publicly through protocol descriptions and shared computational workflows within the NCI Cancer Genomics Cloud. We expect these PDXNet standards to improve the use of PDX and other in vivo models in advancing cancer precision medicine.
Citation Format: The NCI PDXNet Consortium, Yvonne Evrard, Jeffrey H. Chuang. Systematic establishment of robustness and standards in xenograft experiments and analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1054.