bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4300: Cell cycle pathway gene regulation in glioblastoma multiforme (GBM) and GBM derived stem cells: Implicating Pentraxin 3 upregulation
Authors: Wesley Umadevi V. , Clark Paul , Jaeger Jacob , Kuo John , Dempsey Robert 
Published: August 2018

Abstract
Introduction: Glioblastoma Multiforme (GBM) is the most aggressive type of brain cancer and progresses at a rapid rate. The major obstacle in the treatment of GBM is selective survival of a subpopulation of GBM derived stem cells (GSC) which are highly proliferative and resistant to drug induced apoptosis. The proteins involved in the regulation of the cell cycle impact survival potential of GBM and GSCs. Pentraxin 3 (PTX3), an angiogenic and survival factor plays a key role in cell proliferation, angiogenesis and invasion. However, little is known about the association of PTX3 and cell cycle regulation in GBM derived stem cells. Mehods: GBM patient tumor lines, and GSC derived from the same GBM lines were used. These cell lines were exposed to hypoxia and re-oxygenation. Cell cycle profiling and analysis were carried out using flow cytometry and FlowJo Single Cell Data Analysis Software. Xeno-transplanted mouse brain sections were used for PTX3 expression analysis by immunohistochemistry and immunofluorescence staining. Targeted proteomic approach was used to determine PTX3 levels in GBM and GSC. Alterations in the cell cycle regulatory gene expression in GSC and GBM tumor line in presence and absence of PTX3 was identified by transcriptome array analysis. Results: Our targeted proteomic approach using antibody array identified substantially higher levels of PTX3 in GSCs. GBM tumor lines showed higher percent of cells in G1 phase, where as GSCs showed increased number of cells in G2 and S-phase, both under normoxia and hypoxia. GSCs showed increased levels of GADD45A, known to protect GBM cells from apoptosis. Increased PTX3 expression correlated with increased cell cycle progression. Furthermore, exogenous PTX3 increased CyclinD1, a protein required for progression through the G1 phase of the cell cycle. Conclusion: GSC cells show cell cycle progression, presumably with an increased growth advantage. PTX3 expression is associated with GBM malignancy, and may contribute to GBM cell cycle progression and invasion. Overall, these results indicate that PTX3 and the cell cycle pathway are strongly associated with malignant GBM.
Citation Format: Umadevi V. Wesley, Paul Clark, Jacob Jaeger, John Kuo, Robert Dempsey. Cell cycle pathway gene regulation in glioblastoma multiforme (GBM) and GBM derived stem cells: Implicating Pentraxin 3 upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4300.
Abstract 4303: Modulation of protein interaction states through the cell cycle
Authors: Dai Lingyun , Zhao Tianyun , Bisteau Xavier , Sun Wendi , Prabhu Nayana , Lim Yan Ting , Sobota Radoslaw , Kaldis Philipp , Nordlund Pär 
Published: August 2018

Abstract
Global profiling of protein expression through the cell cycle has revealed subsets of periodically expressed proteins. However, expression levels alone only give a partial view of processes determining cellular events. The cell cycle progression events are to a large extent controlled by the dynamic biochemical interactions of proteins with physiological ligands such as other proteins, metabolites, lipids, nucleic acids or low molecular weight effectors. Using a proteome-wide implementation of the Cellular Thermal Shift Assay (CETSA) to study specific cell cycle phases in K562 cell, we uncover modulations of interaction states for more than 750 proteins along the cell cycle. Notably, many protein complexes are modulated in specific cell cycle phases, reflecting their roles in processes such as DNA replication, chromatin remodeling, transcription, translation, and nuclear membrane decomposition. Surprisingly, only small differences in interaction states were seen between G1 and G2 phases, suggesting similar hardwiring of biochemical processes in these two phases. The present work reveals novel molecular details of the cell cycle. CETSA, therefore emerge as a novel approach to discover cellular modulations during cancer development and therapy.
Citation Format: Lingyun Dai, Tianyun Zhao, Xavier Bisteau, Wendi Sun, Nayana Prabhu, Yan Ting Lim, Radoslaw Sobota, Philipp Kaldis, Pär Nordlund. Modulation of protein interaction states through the cell cycle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4303.
Abstract 4314: Chromatin state alterations during melanoma progression
Authors: Rai Kunal , Terranova Christopher , Maitituoheti Mayinuer , Tang Ming , Akdemir Kadir , Orouji Elias , Chin Lynda , Fiziev Petko , Dhamdhere Mayura , Samant Neha S. , Shah Amikhsha , Sharma Sneha , Ernst Jason 
Published: August 2018

Abstract
The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. To determine chromatin state patterns of human metastatic melanomas, we defined epigenome of melanoma by profiling 6 histone modification marks (H3K4me, H3K27Ac, H3K4me3, H3K79me2, H3K27me3 and H3K9me3) in 48 metastatic melanoma tumors, cell lines and short-term cultures. Computation of chromatin states identified specific chromatin state aberrations in human tumors and their relationship with specific genotypes. Specifically, we defined patterns of enhancer elements, broad H3K4me3 domains and bivalent chromatin states enriched in specific genotypes of BRAF, NRAS, and WT groups of melanomas. Importantly, we identified switch from specific bivalent chromatin states in melanocytes to active states leading to upregulation of EMT genes in NRAS mutant melanomas. Similarly, we noted gains of broad H3K4me3 domains in particular classes of oncogenes in specific gentoypes as well as during transitions from melanocytes to melanomas. Finally, we identified clusters of enhancers that are specifically enriched in subset of melanoma samples defining intertumor epigenetic heterogeneity in melanoma tumors. In addition, to investigate chromatin state changes associated with early stages of melanoma progression, we systematically profiled 35 epigenetic modifications in a cell phenotypic model of non-tumorigenic and tumorigenic states (and verified in human nevi and melanoma samples). Specific chromatin state transitions featuring loss of histone acetylations and H3K4me2/3 were observed on specific promoter and enhancer elements targeting cancer-regulatory genes in important melanoma-driving cell signaling pathways. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Overall, our study reveals principles of epigenetic reprogramming in melanoma progression stages and how they may establish transcriptional programs that impart aggressive characteristics to melanomas.
Citation Format: Kunal Rai, Christopher Terranova, Mayinuer Maitituoheti, Ming Tang, Kadir Akdemir, Elias Orouji, Lynda Chin, Petko Fiziev, Mayura Dhamdhere, Neha S. Samant, Amikhsha Shah, Sneha Sharma, Jason Ernst. Chromatin state alterations during melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4314.
Abstract 4318: Identifying drivers of SMARCA4/BRG1-deficient SCCOHT tumorigenesis by integrative multi-omic analysis
Authors: Orlando Krystal A. , Raab Jesse R. , Lang Jessica D. , Hendricks William P. , Wang Yemin , Huntsman David G. , Trent Jeffrey M. , Parker Joel S. , Weissman Bernard E. 
Published: August 2018

Abstract
Over 94% of small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), a rare and aggressive form of ovarian cancer, have mutations and concomitant protein loss in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. SCCOHT tumors rarely have secondary mutations, making them an excellent model for understanding the role BRG1 and SWI/SNF complexes play in tumor suppression. We hypothesize that BRG1 loss drives SCCOHT tumorigenesis by altering chromatin accessibility and gene expression. We have previously shown that BRG1 re-expression in SCCOHT cell lines suppresses cell growth and induces an elongated, neuronal-like morphology. To identify the top genes and transcription factors driving SCCOHT tumorigenesis, we performed ATAC-seq and RNA-seq in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression increased overall chromatin accessibly, shown by an increase in the number of ATAC-seq peaks. ATAC peaks gained following BRG1 re-expression were enriched in transcription factor binding motifs from FOS/JUN/AP-1, TEAD, and SOX family members. RNA-seq analysis demonstrated that BRG1 re-expression upregulated more genes than those downregulated, consistent with the increase in ATAC-seq peaks. Preliminary pathway analysis identified gene enrichments in epithelial-mesenchymal transition pathway and extracellular matrix remodeling following BRG1 re-expression, consistent with the observed morphology change. Cell types enrichment analysis (xCell) identified a shift from a mesenchymal stem cell-like gene signature in the control SCCOHT cells to an epithelial cell-like gene signature following BRG1 re-expression, further suggesting a possible mesenchymal-epithelial transition in SCCOHT cells after BRG1 re-expression. Future studies include integration of the ATAC/RNA-seq data to further identify correlations between gene expression changes and enriched transcription factor binding motifs, integrative ChIP-seq analysis for BRG1 following re-expression, and proteomic analyses. These studies will uncover the key genes, proteins, and transcription factors affected by BRG1 loss in other adult cancers, provide insight into BRG1's role in SCCOHT tumorigenesis, and potentially yield novel therapeutic targets.
Citation Format: Krystal A. Orlando, Jesse R. Raab, Jessica D. Lang, William P. Hendricks, Yemin Wang, David G. Huntsman, Jeffrey M. Trent, Joel S. Parker, Bernard E. Weissman. Identifying drivers of SMARCA4/BRG1-deficient SCCOHT tumorigenesis by integrative multi-omic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4318.
Abstract 4321: Up-regulation of METTL3 promoted m6A modification and epigenetic silencing of SOCS2 in human liver cancer
Authors: Chen Mengnuo , Wei Lai , Law Cheuk-Ting , Tsang Felice H. , Shen Jialing , Cheng Carol L. , Tsang Long-Hin , Ho Daniel W. , Chiu David K. , Lee Joyce M. , Wong Carmen C. , Ng Irene O. , Wong Chun-Ming 
Published: August 2018

Abstract
Epigenetic alteration is a common trait of human cancers. Chemical modifications on DNA and core histone proteins are the major mechanisms for epigenetic regulation. Recently, emerging evidence suggested that reversible chemical modifications on RNA also play a critical role in epigenetic control of gene expression. N6-methyladenosine (m6A) is the most abundant modification found in mammalian mRNA. m6A is involved in regulating mRNA stability, splicing, and translation. However, the implications of m6A modification in human carcinogenesis remain poorly understood. In this study, we investigated the expression of m6A methyltransferases and demethylases in human hepatocellular carcinoma (HCC). We found the major m6A methyltransferase METTL3 was remarkably up-regulated in HCC. High METTL3 expression was associated with poor overall and disease-free survival in HCC patients. Consistent with the METTL3 overexpression, we found that mRNA m6A level was significantly elevated in human HCC. To investigate the roles of METTL3 in human HCC, we employed lentiviral-based shRNA and CRISPR/Cas9 systems to inactivation METTL3 in HCC cell lines. We showed that knockdown and knockout of METTL3 drastically suppressed HCC proliferation and migration in vitro and abolished HCC tumorigenicity and lung metastasis in vivo. In contrast, overexpression of METTL3 by CRISPR/dCas9 SAM system promoted HCC growth. Using RNA-seq and m6A-Seq, we identified tumor suppressor gene SOCS2 as a novel target of METTL3. We detected m6A modification in SOCS2 mRNA and the m6A modification was diminished upon METTL3 knockdown. m6A modification promoted SOCS2 mRNA degradation. We demonstrated that knockdown of METTL3, mutation of m6A modification sites, and treatment of demethylating agent augmented SOCS2 mRNA expression in HCC cells. In addition, knockdown of YTHDF2, an m6A reader protein, also rescued SOCS2 mRNA expression in HCC cells. The above findings together demonstrated that up-regulation of METTL3 lead to m6A modification of SOCS2, which in turn promotes SOCS2 mRNA degradation through YTHDF2 dependent mechanism. Our findings provided a proof-of-concept model to demonstrate the importance of aberrant m6A modification in epigenetic silencing of tumor suppressor genes.
Citation Format: Mengnuo Chen, Lai Wei, Cheuk-Ting Law, Felice H. Tsang, Jialing Shen, Carol L. Cheng, Long-Hin Tsang, Daniel W. Ho, David K. Chiu, Joyce M. Lee, Carmen C. Wong, Irene O. Ng, Chun-Ming Wong. Up-regulation of METTL3 promoted m6A modification and epigenetic silencing of SOCS2 in human liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4321.
Abstract 4322: Atrx inactivation drives motility and dysregulates differentiation in glioma cells of origin through global epigenomic remodeling
Authors: Danussi Carla , Bose Promita , Silberman Pedro , Arnam John S. Van , Vitucci Mark , Tang Oliver , Heguy Adriana , Chan Timothy A. , Sulman Erik P. , Lang Frederick , Creighton Chad J. , Deneen Benjamin , Miller C Ryan , Picketts David J. , Kannan Kasthuri , Huse Jason T. 
Published: August 2018

Abstract
Comprehensive genomic profiling in cancer continues to reveal frequent alterations in epigenetic regulators, firmly implicating chromatin biology in the oncogenic process. For instance, genetic inactivation of the SWI/SNF chromatin regulator ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in both adult and pediatric malignant glioma, and occurs frequently in other cancers as well. ATRX deficiency has been linked to a wide spectrum of physiological dysfunction, including aberrant gene regulation, abnormal telomere maintenance, genomic instability, and aneuploidy. However, the precise oncogenic mechanism(s) induced by ATRX deficiency remain unclear, particularly those involving epigenomic dysregulation. To model these events in putative glioma cells of origin, we inactivated Atrx in primary murine neuroepithelial progenitors (mNPCs). Atrx loss, especially when coupled with Tp53 inactivation, promoted mNPC motility while also modulating differentiation state and potential, effectively recapitulating characteristic disease phenotypes and molecular features. Moreover, these phenotypes correlated with altered gene expression profiles in functionally relevant molecular networks (e.g. cell differentiation and migration). Integrating these transcriptional changes with shifts in chromatin accessibility occurring with Atrx deficiency, along with genome-wide Atrx distribution as determined by ChIP-seq, revealed highly significant spatial correlations between differentially expressed genes, regions of altered chromatin compaction, and genomic sites normally occupied by Atrx. Finally, target genes mediating specific Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate cellular and molecular contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes.
Citation Format: Carla Danussi, Promita Bose, Pedro Silberman, John S. Van Arnam, Mark Vitucci, Oliver Tang, Adriana Heguy, Timothy A. Chan, Erik P. Sulman, Frederick Lang, Chad J. Creighton, Benjamin Deneen, C Ryan Miller, David J. Picketts, Kasthuri Kannan, Jason T. Huse. Atrx inactivation drives motility and dysregulates differentiation in glioma cells of origin through global epigenomic remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4322.
Abstract 4329: Enhancer mapping in triple-negative breast cancer as a tool for novel biomarker and oncogene discovery
Authors: Raisner Ryan , Bainer Russ , Gascoigne Karen 
Published: August 2018

Abstract
Breast cancer is the most commonly diagnosed cancer in women, affecting ~8% of women in the U.S. in their lifetime. Triple-negative breast cancer (TNBC) represents a heterogeneous class of aggressive cancers that comprise 15-20% of all breast cancers. TNBCs characteristically do not have significant levels of estrogen receptor (ER), progesterone receptor (PR), or overexpression of human epidermal growth factor 2 (HER-2). Consequently, there is a lack of proven drug therapies and biomarkers for TNBC. Here we have used ChIP-SEQ combined with RNA-SEQ to profile TNBC cell lines for their super-enhancer patterns. These noncoding, trans-acting elements control gene expression and play an essential role in the establishment and maintenance of cell states. It has been suggested that a wide range of cancers arise in part due to enhancer dysregulation, and key oncogenes genes coming under control of super-enhancers. This can occur through translocations, amplifications, or creation of de novo transcription factor binding sites. We hypothesize that mapping tumor-specific super-enhancer patterns in TNBC will identify novel tumor-specific gene-regulatory networks, and dysregulated genes that contribute uniquely to the development of tumors. We have conducted a CRISPR-mediated drop-out screen on a number of TNBC cell lines for genes that are controlled by cancer-specific super-enhancers with the hope of identifying novel oncogenic drivers.
Citation Format: Ryan Raisner, Russ Bainer, Karen Gascoigne. Enhancer mapping in triple-negative breast cancer as a tool for novel biomarker and oncogene discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4329.
Abstract 4355: Identification and functional characterization of glioma structural variants
Authors: Johnson Kevin C. , Barthel Floris P. , Tang Ming , Amin Samirkumar , Wang Qianghu , Sulman Erik P. , Rai Kunal , Verhaak Roel G.W 
Published: August 2018

Abstract
Adult diffuse gliomas are a diverse class of brain tumors that ultimately result in fatal malignant progression. The highly variable disease progression intervals and poor treatment response observed in glioma have been explained, in part, by the extent of heterogeneity within and across gliomas. Somatic structural variants such as deletions, duplications, insertions, inversions, translocations, and extrachromosomal DNA contribute to glioma heterogeneity by generating genomic instability, a hallmark of cancer genomes. While comprehensive approaches such as whole genome sequencing have begun to catalog the glioma structural variant landscape, the molecular mechanisms by which they contribute to tumor progression remains poorly understood. Here, we identified genomic rearrangements in the whole genomes of 147 gliomas and glioma cell lines. Among the whole-genome sequencing samples were 62 glioblastomas (TCGA), 52 low-grade gliomas (TCGA), and our own set of 33 patient-derived glioma sphere-forming cells. On average, glioblastomas demonstrated a greater frequency of high-confidence structural variants (162 per tumor) than low-grade gliomas (130 per tumor, P=0.02) with two glioblastomas displaying evidence of chromothripsis. Across the World Heath Organization's molecular classifications, the IDH-mutant 1p/19q co-deleted tumors demonstrated the lowest structural variant burden when compared with both IDH-wildtype and IDH-mutant non-co-deleted tumors. Structural variant frequencies were found to be similar between patient tumors and an independent set of patient-derived cell lines. Across all samples, a majority of the structural variant breakpoints were found in intronic (42%) and intergenic regions (55%) suggesting that rearrangements predominantly impact distal regulatory regions. To investigate the functional consequences of structural variants in these regions we integrated these samples with available RNA-sequencing and epigenetic data to characterize deregulated transcriptional circuits. Analyses examining the association between genomic rearrangements and chromatin states to determine potential mechanisms of oncogene activation in select tumor and cell line samples are now underway. Together, our study demonstrates the importance of integrating structural variant calls from whole genome sequencing with expression and epigenetic data to define functional genomic rearrangements.
Citation Format: Kevin C. Johnson, Floris P. Barthel, Ming Tang, Samirkumar Amin, Qianghu Wang, Erik P. Sulman, Kunal Rai, Roel G.W Verhaak. Identification and functional characterization of glioma structural variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4355.
Abstract 4374: Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia
Authors: Chong Phyllis SY , Zhou Jianbiao , Chooi Jing Yuan , Chng Wee Joo , Gunaratne Jayantha , Zeng Qi 
Published: August 2018

Abstract
Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for the dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients subset who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation.
Citation Format: Phyllis SY Chong, Jianbiao Zhou, Jing Yuan Chooi, Wee Joo Chng, Jayantha Gunaratne, Qi Zeng. Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4374.