bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA04: Understanding tumor heterogeneity in glioblastoma
Authors: Tavaré Simon , Sottoriva Andrea , Piccirillo Sara , Spiteri Inma , Touloumis Anestis , Marioni John C. , Curtis Christina N. , Watts Colin 
Published: May 2016

Abstract
Glioblastoma (GB) is advanced at the time of clinical presentation and response to treatment may be confounded by clonal heterogeneity and differential patterns of resistance in spatially distinct parts of the same tumor. However, we do not understand how this complex environment evolves. Accumulating evidence suggests that intra-tumor heterogeneity is likely to be the key to understanding treatment failure, however the dynamics of such heterogeneity are still poorly understood.
Using a Fluorescence-Guided Multiple Sampling technique we obtained samples from the tumor mass, the sub-ependymal zone and the non-fluorescent tumor margin. We performed an integrated genomic analysis to develop a spatial reconstruction of tumor evolution in individual patients. Temporal analysis was performed using patient-derived xenografts obtained by serial transplantation of tumor cells in immuno-suppressed mice.
Phylogenetic reconstruction of the fragments from each GB identifies copy number alterations in EGFR and CDKN2A/B/p14ARF as early evolutionary events while aberrations in PDGFRA and PTEN occur later in the disease progression. Transcriptional profiling reveals that many patients display multiple GB subtypes within their tumor while deconstruction of the clonal organization of each tumor fragment at single-molecule level identified multiple coexisting cell lineages. Ancestral tumor precursors that gave rise to the tumor mass were found in the sub-ependymal zone of a subset of GB patients. When used in in vivo experiments, tumor cells show variable competitive capacity for disease propagation and further genetic diversification, suggesting that GB evolves through complex dynamics of sub-clonal fitness advantage and acquisitions of mutations and copy number alterations.
Our integrated genomic analysis addresses the evolution of GB in individual patients across multiple spatial scales. Our data reveal early clonal diversification generating a genetically complex and highly evolved disease environment at clinical presentation. We propose that these fundamental patient-specific tumor evolutionary dynamics underlie clinical phenotypic heterogeneity and may have implications for the emergence of resistant disease.
Citation Format: Simon Tavaré, Andrea Sottoriva, Sara Piccirillo, Inma Spiteri, Anestis Touloumis, John C. Marioni, Christina N. Curtis, Colin Watts. Understanding tumor heterogeneity in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA04.
Abstract IA17: Genome-epigenome interplay in medulloblastoma
Authors: Northcott Paul A. 
Published: May 2016

Abstract
The recent application of genomics to large series of primary human medulloblastomas has dramatically improved our perspective of the genes, pathways, and molecular processes underpinning this highly malignant pediatric brain tumor. Transcriptionally defined molecular subgroups have emerged, changing the fundamental definition of medulloblastoma from a single histologically recognized entity, to four distinct subtypes: WNT, SHH, Group3, and Group4. These subgroups exhibit highly discriminatory genomic landscapes, patient demographics, and clinical phenotypes. Next-generation sequencing has identified and implicated recurrently altered somatic drivers, many of which are affected in a subgroup-restricted manner. In contrast, somatic variants affecting chromatin-modifying genes, including histone “writers,” “erasers,” and “readers” are prevalent in medulloblastoma and occur across subgroups, suggesting that deregulation of the epigenome is an essential step during medulloblastoma development. Integrative “omics”-based strategies have begun to dissect the fascinating genome-epigenome interplay underlying medulloblastoma, revealing previously undisclosed oncogenic mechanisms and drivers of disease. Furthermore, new insights into the biology and putative origins of the poorly understood Group3 and Group4 medulloblastomas have likewise been revealed. This talk will summarize these recent discoveries afforded through genomics and discuss their potential implications, both in the lab and in the clinic, going forward.
Citation Format: Paul A. Northcott. Genome-epigenome interplay in medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA17.
Abstract A03: Krüppel-like Transcription Factor-10 (KLF10) suppresses the TGFβ-induced epithelial-to-mesenchymal transition
Authors: Mishra Vivek Kumar , Kari Vijayalakshmi , Subramaniam Malayannan , Baumgart Simon J. , Nagarajan Sankari , Wegwitz Florian , Spelsberg Thomas C. , Hawse John R. , Johnsen Steven A. 
Published: May 2016

Abstract
The Transforming Growth Factor-β (TGFβ)/SMAD signaling pathway can function as either a tumor suppressor or metastasis promoter during tumor progression. In normal epithelial cells and early stages of epithelial tumorigenesis TGFβ functions as a tumor suppressor to decrease cell proliferation or induce apoptosis. However, during malignant progression tumor cells no longer respond to the anti-proliferative effects of TGFβ, but instead undergo an epithelial-to-mesenchymal transition (EMT) whereby cells acquire a migratory and invasive phenotype which promotes tumor metastasis. Resolution of the dichotomy in TGFβ function and a further understanding of its tumor suppressor and metastasis promoting functions may uncover new strategies for the treatment of epithelial cancers. In previous studies we demonstrated an important role of the TGFβ-Inducible Early Gene-1 (TIEG1)/Krüppel-like Factor-10 (KLF10) as a central regulator of TGFβ/SMAD signaling and the anti-proliferative functions of TGFβ. In this study we examined the role of KLF10 in controlling the TGFβ-induced EMT in human lung adenocarcinoma cells. We show that depletion of KLF10 results in a more pronounced induction of EMT in human A549 lung adenocarcinoma cells as assessed by quantitative real-time PCR, changes in cellular morphology and immunofluorescence microscopy, and transcriptome-wide (RNA-seq) analyses. Moreover, chromatin immunoprecipitation (ChIP) and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis shows that KLF10 directly binds to GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2 to repress its transcription. Consistent with these findings, an analysis of KLF10 and SNAI2 expression in lung cancer revealed that while KLF10 levels are decreased in lung cancer vs. normal samples, SNAI2 levels are increased. Additional ChIP studies showed that KLF10 recruits HDAC1 to the SNAI2 promoter and is required for the removal of activating histone acetylation marks. These findings reveal a previously unknown function of KLF10 in suppressing TGFβ-induced EMT and represent a significant advancement in the understanding the molecular dichotomy of TGFβ function during tumor progression.
Citation Format: Vivek Kumar Mishra, Vijayalakshmi Kari, Malayannan Subramaniam, Simon J. Baumgart, Sankari Nagarajan, Florian Wegwitz, Thomas C. Spelsberg, John R. Hawse, Steven A. Johnsen. Krüppel-like Transcription Factor-10 (KLF10) suppresses the TGFβ-induced epithelial-to-mesenchymal transition. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A03.
Abstract A04: Modulation of SAGA mediated nucleosome acetylation by linker DNA and activator
Authors: Mittal Chitvan 
Published: May 2016

Abstract
The SAGA family of co-activators are highly conserved eukaryotic protein complexes that play a major role in regulating gene expression. These complexes facilitate transcription of inducible genes, in part, by acetylating the histone H3 tails of nucleosomes. While the factors that influence nucleosome acetylation are qualitatively understood, quantitative approaches offer the potential to better understand how the interaction between complex nucleosomal substrates, a multi-subunit SAGA complex, and regulatory proteins, combine to remodel the chromatin landscape of gene promoters. Toward this end, we have developed an initial rate, steady-state, acetylation assay using immobilized nucleosomes. For a minimal 147 bp mononucleosome, we find that acetylation activity saturates at a low nucleosome concentration (50 nM KM), and that turnover is quite slow (0.25 min-1 kcat). Addition of linker DNA to the nucleosome enhances acetylation activity up to 8-fold, and does so both by changing the apparent binding constant (2x decrease in KM) and the turnover step (4x increase in kcat). This dual mechanism of stimulation is recapitulated by addition of free DNA in trans, and we are investing the minimum lengths of DNA required for stimulation, as well as the mechanism of stimulation. When the transcriptional activator Gal4-VP16 becomes bound specifically to a recognition site within the linker DNA, additional stimulation of acetylation activity is observed. We are currently working towards gaining more insights into the mechanistic basis of this effect. The results give a more in depth perspective of how different factors work in conjunction to ultimately tune inducible transcription.
Citation Format: Chitvan Mittal. Modulation of SAGA mediated nucleosome acetylation by linker DNA and activator. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A04.
Abstract A13: Androgen receptor functions as an adaptor protein for recruitment of protein phosphatase 1a to chromatin and CDK9 mobilization
Authors: Liu Xiaming , Gao Yanfei , Cai Changmeng , Balk Steven , Chen Shaoyong 
Published: May 2016

Abstract
The androgen receptor (AR) plays a central role in prostate cancer (PCa) development and progression. AR activity can be modulated by phosphorylation at multiple sites, with S81 phosphorylation mediated by CDK9 playing a particularly important role that may be due to enhancing recruitment of the coactivator p300. The CDK9/cyclin T complex (P-TEFb) is recruited to enhancer/promoter sites by BRD4, where it phosphorylates NELF and RNA polymerase 2 to stimulate transcriptional elongation. A large fraction of P-TEFb is held in an inactive state by association with a 7SK RNA complex, and can be released from this complex through dephosphorylation of CDK9 by protein phosphatase 1 (PP1). The major isoform of the PP1 catalytic subunit, PP1a, associates with a large number of regulatory proteins that target it to specific sites. PNUTS is a regulatory protein targeting PP1a to chromatin, but additional mechanisms that may target PP1a to chromatin to mediate CDK9 dephosphorylation and drive transcriptional elongation remain to be identified. We reported previously that AR could interact with PP1a, and that PP1a could enhance AR activity by dephosphorylating S650 in the AR hinge region and thereby prevent its nuclear export. In this study we show by chromatin immunoprecipitation that AR also recruits PP1a to androgen-stimulated enhancers, and show that PP1a inhibition with tautomycin prevents P-TEFb recruitment to AR-regulated genes and CDK9-mediated phosphorylation of RNA polymerase 2. We further show that PP1a binds to the AR ligand binding domain independently of ligand, and that this binding is negatively regulated by the androgen induced AR N/C-terminal interaction. Significantly, the AR N/C interaction impairs AR recruitment of coactivators prior to chromatin binding, but is disrupted on chromatin to enhance coactivator recruitment, which would also facilitate recruitment of PP1a. These findings indicate that AR functions as a PP1a regulatory protein targeting PP1a to chromatin, and thereby identify a novel mechanism for the selective recruitment of PP1a to a specific subset of genes where it can drive transcriptional elongation, and may also regulate mRNA splicing.
Citation Format: Xiaming Liu, Yanfei Gao, Changmeng Cai, Steven Balk, Shaoyong Chen. Androgen receptor functions as an adaptor protein for recruitment of protein phosphatase 1a to chromatin and CDK9 mobilization. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A13.
Abstract A21: The role of SOX4 in epithelial to mesenchymal transition in prostate cancer
Authors: Sharma Nitya V. , Sannigrahi Soma , Lai YuHeng , Moreno Carlos 
Published: May 2016

Abstract
Prostate cancer remains the most commonly diagnosed cancer in U.S. males, and ranks second in mortality with over 28,000 deaths per year. Prostate cancer mortality is typically due to metastases, necessitating the understanding of how metastatic disease develops. One major step for cancer cells to metastasize and acquire migratory and invasive capabilities is the epithelial to mesenchymal transition (EMT). EMT encompasses vast molecular changes in gene expression, mediated by aberrant developmental signaling pathway activation, leading to the loss of cell-cell junctions and planar and apical-basal polarity, increased motility, and resistance to apoptosis and anoikis (cell death due to the detachment from the extracellular matrix). The sex determining region Y-box 4 (SOX4) gene is a developmental transcription factor that is over expressed in prostate cancer and plays a critical role in many developmental pathways inappropriately activated during EMT, such as the transforming growth factor (TGF-beta) and epidermal growth factor receptor (EGFR) signaling pathways. Our data suggest that concomitant treatment of TGF-beta and EGF induces SOX4, and initiates the EMT program in prostate epithelial cell lines. We also demonstrate that SOX4 over expression is sufficient to induce EMT in prostate epithelial cell lines. Currently, the molecular mechanisms that govern how SOX4 initiates EMT via transcriptional activation of target genes are poorly understood. We identified candidate SOX4 targets using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE) on 9755 Pan Cancer samples from The Cancer Genome Atlas (TCGA). Gene ontology analysis of the top 1000 candidate SOX4 targets revealed genes that were enriched for epigenetic processes such as chromatin modification and DNA methylation. One putative target gene, PCAF, is a subunit of a large histone acetyltransferase (HAT) complex. Interestingly, our preliminary data also suggest that SOX4 interacts not only with PCAF, but also with TRRAP, another subunit of the PCAF HAT complex. These data suggest that SOX4 may induce and recruit the PCAF/TRRAP HAT complex in order to transcriptionally activate downstream targets to initiate the EMT program.
Citation Format: Nitya V. Sharma, Soma Sannigrahi, YuHeng Lai, Carlos Moreno. The role of SOX4 in epithelial to mesenchymal transition in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A21.
Abstract A37: Aberrant DNA methylation of HTATIP2 and UCH-L1 as prognostic and predictive biomarkers for cholangiocarcinoma
Authors: Limpaiboon Temduang , Nanok Chaiyachet , Proungvitaya Siriporn , Jearanaikoon Patcharee , Pugkhem Ake , Puapairoj Anucha 
Published: May 2016

Abstract
Cholangiocarcinoma (CCA) is a malignancy of bile duct epithelial cell lining. In the past decade, the incidence and mortality rates of CCA have been increasing worldwide. The effective treatment modality for CCA is surgical resection. Adjuvant chemotherapy and/or radiotherapy are optional therapy for unresectable and postoperative CCA. Unfortunately, the responsiveness of CCA patients to chemotherapy was relatively low and 5-year survival rate was poor. We have analyzed data which were obtained from our previous study on methylation microarray based on chemotherapeutic drug resistance and found aberrant DNA methylation of genes related to chemotherapy. This present study aimed to quantitate DNA methylation levels of 10 candidate genes related to chemotherapy in 54 CCA and 19 normal adjacent tissues using methylation-sensitive high resolution melting (MS-HRM) analysis. The methylation level of each gene was statistically analyzed with clinical parameters. Genes with high methylation level were UCH-L1 and IRF4, and genes with moderate methylation were CCND2, HTATIP2 and TP53I3. We found significant difference in methylation levels of HTATIP2 (P=0.036) and UCH-L1 (P=0.012) between short and long survival groups. Patients with high methylation level of HTATIP2 and low methylation of UCH-L1 showed longer overall survival (P=0.03 and P=0.044, respectively). Interestingly, chemotherapeutic responders showed higher methylation level of HTATIP2 than non-responders (P=0.020), whereas no significant difference in UCH-L1 methylation level was observed between these two groups. The methylation levels of HTATIP2 and UCH-L1 were low in normal adjacent tissues. In patients who received chemotherapy, patients who had high methylation of HTATIP2 and low methylation of UCH-L1 showed longer overall survival (P&lt;0.001 and P=0.041, respectively). Moreover, HTATIP2 methylation was associated with tumor progression in which lower methylation level was found in CCA patients with positive lymph node metastasis (P=0.029). In conclusion, our finding indicates the great value of DNA methylation levels of HTATIP2 and UCH-L1 as prognostic and predictive markers for CCA patients.
Citation Format: Temduang Limpaiboon, Chaiyachet Nanok, Siriporn Proungvitaya, Patcharee Jearanaikoon, Ake Pugkhem, Anucha Puapairoj. Aberrant DNA methylation of HTATIP2 and UCH-L1 as prognostic and predictive biomarkers for cholangiocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A37.
Abstract A43: DNA repair by non-homologous end joining induced gene silencing via DNA hypermethylation
Authors: Allen Brittany N. , Masternak Michal , Muller Mark 
Published: May 2016

Abstract
Double strand breaks (DSBs) in DNA are repaired throughout the cell cycle and in non-dividing cells by the error-prone process of non-homologous end joining (NHEJ). In order to evaluate expression of a gene following NHEJ repair, we use a GFP reporter system to allow for targeted induction of a DSB in the genome of Hela cells. Prior to induction of the DSB, GFP is transcribed but inactive due to an extra exon interrupting the gene sequence, however cells that successfully repair the DSB express WT GFP that can be detected by fluorescent based assays. Following repair, two different GFP expression classes can be detected by flow cytometry: one that expresses GFP robustly (‘bright') and one that expresses GFP at a lower level (‘dim'). This is surprising given that these experiments are done in a cell line derived from a single clone. This phenomenon was confirmed using live cell imaging. Treatment with a hypomethylating drug causes some ‘dim' cells to be converted to ‘bright' cells, suggesting that the gene silencing that occurs in the ‘dim' population is a result of hypermethylation of the gene. Bisulfite deep sequencing confirms that areas up- and downstream of the break site are hypomethylated in ‘bright' cell populations and hypermethylated in ‘dim' cell populations. It can be concluded from these data that, following repair of a DSB by NHEJ, the epigenetic landscape of the repaired gene, specifically the methylation status of its CpGs, is altered in a way that changes the expression levels of the repaired gene. Though their cause is not fully understood, gene expression changes caused by epigenetic reprogramming are a hallmark of many different types of cancer. Given the increased reliance of cancer cells on DNA repair, a link between epigenetic revision and DNA repair could provide an explanation for changes in the epigenome that occur during cancer progression.
Citation Format: Brittany N. Allen, Michal Masternak, Mark Muller. DNA repair by non-homologous end joining induced gene silencing via DNA hypermethylation. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A43.
Abstract A50: The identification of an Ets1-driven gene signature in head and neck squamous cell carcinoma
Authors: Gluck Christian , Sethi Isha , Tsompana Maria , Sinha Satrajit 
Published: May 2016

Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous disease of significant mortality and morbidity and with limited treatment options. This highlights the urgent need for a better understanding of the underlying biology of HNSCC. Recent genomic analysis of HNSCC tumors has identified four distinct molecular classes, of which the mesenchymal subtype is particularly aggressive in nature and associated with poor survival. We have discovered that Ets1, a prototypic oncogenic transcription factor, is selectively enriched in the mesenchymal HNSCC tumors along with other key drivers of Epithelial to Mesenchymal transition (EMT). Further analysis of gene expression datasets reveals that Ets1 expression, while low in normal epithelium, increases in pre-malignant and malignant tissues, suggesting a possible role for Ets1 during early tumorigenesis. Strikingly, Kaplan Meier analysis shows that Ets1 expression is associated with both poor survival in HNSCC and high incidence of tumor recurrence. We have performed hierarchical clustering of 33 HNSCC cell lines to show that these cell lines exhibit gene expression profiles that are representative of the four tumor subtypes. To better understand the Ets1-driven molecular processes in EMT high tumors, we have utilized SCC25, a mesenchymal HNSCC cell line to perform global transcriptomic analysis of effects of Ets1 knockdown. Additionally, we have also performed ChIP-seq experiments to identify genome wide transcriptional targets of Ets1 in SCC25. Taken together, these studies have uncovered an Ets1 intrinsic core gene signature that can serve as a valuable tool for further tumor classification and cancer-specific pathway discovery. Interestingly, by cross-referencing with the Cancer Genome Atlas HNSCC RNA-Seq dataset, we demonstrate that Ets1 expression is highly correlated with the majority of the Ets1 signature target genes thus reinforcing a functional relationship. Collectively, our findings not only identify several Ets1 dependent genes that are key to initiating and maintaining EMT in HNSCC, but also unearth novel targets that can be exploited for future therapeutics against this deadly cancer.
Citation Format: Christian Gluck, Isha Sethi, Maria Tsompana, Satrajit Sinha. The identification of an Ets1-driven gene signature in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A50.