tbuckley/cabot-search huggingface dataset:
Abstract 308: The PP2A-B56 phosphatase opposes cyclin E autocatalytic degradation via site-specific dephosphorylation
Authors: Ryan J. Davis, Jherek Swanger, Bruce E. Clurman
Journal: Cancer Research (2017)

Abstract Cyclin E, in conjunction with its catalytic partner cyclin-dependent kinase 2 (CDK2), regulates cell cycle progression as cells exit quiescence and enter S-phase. Multiple mechanisms control cyclin E-CDK2 activity during the cell cycle, including phosphorylation-dependent cyclin E ubiquitylation by the SCFFbw7 ubiquitin ligase. Serine 384 (S384) is the critical cyclin E phosphorylation site that stimulates Fbw7 binding and subsequent cyclin E degradation. Because S384 is autophosphorylated by CDK2, cyclin E therefore instigates its own degradation in an autocatalytic manner. This presents a paradox as to how cyclin E-CDK2 is able to phosphorylate its numerous substrates prior to cyclin E autophosphorylation-catalyzed degradation. Here we find that the PP2A-B56 phosphatase specifically dephosphorylates cyclin E at S384, thereby uncoupling cyclin E degradation from cyclin E-CDK2 activity. Furthermore, the rate of S384 dephosphorylation is high in interphase and low in mitosis, allowing PP2A-B56 to oppose autocatalytic cyclin E degradation and maintain cyclin E-CDK2 activity at the G1/S transition. Citation Format: Ryan J. Davis, Jherek Swanger, Bruce E. Clurman. The PP2A-B56 phosphatase opposes cyclin E autocatalytic degradation via site-specific dephosphorylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 308. doi:10.1158/1538-7445.AM2017-308
Abstract 775: Identification of activated signal transduction pathways and molecules in the HMGB-1 induced angiogenesis
Authors: Yujin Kwon, Sujin Shin, Won Kyu Kim, Hoguen Kim
Journal: Cancer Research (2017)

Abstract High-mobility group box-1 (HMGB-1) is a highly conserved protein playing various roles both in the nucleus and cytosol and known to be expressed in almost all types of mammalian cells. Secreted HMGB-1 has been most intensively studied and reported as an immune cell derived cytokine regulating systemic inflammation, signal transduction, and activation of endothelial cells (EC). Especially, HMGB-1 over-expression is now considered as a hallmark in cancers based on its involvement in cell proliferation, inflammatory microenvironment, invasion, metastasis, and sustained angiogenesis. Numerous studies have shown that secreted HMGB-1 directly or indirectly promotes angiogenesis by activation of ECs. However, mechanisms of HMGB-1 mediated angiogenesis have not yet been fully understood, especially, in terms of genomic changes caused by HMGB-1 treatment. Moreover, differences between vascular endothelial growth factor (VEGF) mediated and HMGB-1 mediated angiogenesis have not been studied. To explore the roles of HMGB-1 in angiogenesis, we first confirmed whether HMGB-1 treatment renders ECs angiogenic by evaluating proliferation, migration, wound-healing, and tubule formation of ECs after HMGB-1 treatment. In addition, we performed gene expression microarray to clarify how HMGB-1 treatment induced EC activation at various time points and subsequent angiogenic features according to time-dependent gene expression changes. We show that HMGB-1 treatment induces proangiogenic features to ECs such as stimulation of tubule formation, promotion of proliferation, and accelerated wound healing. By analysis of microarray data, we found that VEGF and HMGB-1 commonly promoted the activation of MAPK, cell proliferation, and wound healing pathways which directly regulate angiogenesis. On the other hand, axon guidance, gap junction, P53 signaling, cell cycle, and cell differentiation pathways were specifically up-regulated by HMGB-1. Taken together, HMGB-1 leads to angiogenesis via upregulation of both angiogenic and nonangiogenic genes. Citation Format: Yujin Kwon, Sujin Shin, Won Kyu Kim, Hoguen Kim. Identification of activated signal transduction pathways and molecules in the HMGB-1 induced angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 775. doi:10.1158/1538-7445.AM2017-775
Abstract SY22-03: Multi-omics analysis of paired normal and tumor tissues reveals when and what causes altered metabolism in colorectal cancer
Authors: Tomoyoshi Soga
Journal: Cancer Research (2017)

Abstract Metabolic reprogramming is a common hallmark of cancer. Most cancer cells produce ATP and the precursors of biomass (e.g., nucleotides, amino acids, and lipids) by shifting from oxidative phosphorylation to aerobic glycolysis, commonly known as the “Warburg effect.” Recently these cancer-specific metabolic pathways have been considered as attractive targets for cancer therapy. However, the mechanisms underlying the control of cancer cell metabolism are poorly understood. To address underlying mechanisms that induce metabolic reprogramming of cancer metabolism, we applied capillary electrophoresis mass spectrometry (CE-MS) metabolic profiling to paired normal tissues and tumor tissues obtained from 275 patients with colon cancer. Significant changes in the levels of many metabolites were observed between normal and tumor tissues. Unexpectedly, metabolite levels altered quite early and remained unchanged among cancer stages. S-Adenosylmethionine (SAM) was the most increased metabolite. Glucose was the second most decreased metabolite in tumor tissues, whereas lactate, the final product of glycolysis, was increased, which indicates activation of glycolysis (the Warburg effect). We then applied transcriptome analysis to paired normal-cancer colon tissues and revealed that alterations in mRNA levels also occurred at the adenoma stage. Regarding energy metabolism, mRNAs encoding glycolysis purine/pyrimidine synthesis, one-carbon metabolism, and fatty acid synthesis were highly expressed, whereas those in fatty acid oxidation were down-regulated in tumor tissue. Colon cancer is associated with mutations in oncogenes and tumor suppressor genes such as adenomatous polyposis coli (APC), Kirsten-ras (KRAS), and TP53. We applied next-generation sequencing technologies for the detection of somatic mutations to the tumor tissues and found mutation frequencies of 78% in APC, 68% in TP53, and 48% in KRAS. Similar to metabolome and transcriptome data, these mutations were umbiased among cancer stages. We investigated whether gene mutations including APC, KRAS, and TP53 mutations affected metabolism. Regardless of the presence or absence of the mutations, the levels of most metabolites were unaltered in tumor tissues. This raises the question of which molecules contribute to the regulation of metabolic reprogramming of colorectal cancer metabolism. Citation Format: Tomoyoshi Soga. Multi-omics analysis of paired normal and tumor tissues reveals when and what causes altered metabolism in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY22-03. doi:10.1158/1538-7445.AM2017-SY22-03
Abstract 3352: Genome-wide enhancer identify signature predictive of metastatic phenotypes in bladder cancers
Authors: Sohyoung Kim, Lyuba Varticovski, Qizong Lao, Songjoon Baek, Michael L. Nickerson, Myong-Hee Sung, Lars Grontved, Thompson Bethtrice, Dan Theodorescu, Piyush K. Agarwal, Michael Dean, Gordon Hager
Journal: Cancer Research (2017)

Abstract In urothelial bladder cancer accurate identification of grade and stage is critical for optimal treatment to achieve robust disease control and long-term survival. However, among the initially superficial tumors, which are non-invasive and highly treatable, 20 to 25 % recur, progress to invasive tumors, and metastasize during the patients’ lifetime. Thus, the challenge is to provide risk stratification during the initial diagnosis in order to identify those patients who are unlikely to progress while offering radical therapy to those who are at risk. To address this issue, the field has heavily focused on the discovery of few mutations in potential driver genes. However, recent findings indicate that deregulation of enhancers can play a major role in cancer progression. In this study, we employed DNase-Seq to detect enhancer activities genome-wide in 16 bladder cancer cell lines (BLCs) that included three lineages (T24, UMUC3, 253J lineages) with different tumorigenic and metastatic potentials, and thus represent models of cancer progression and metastasis development. We analyzed the gain and loss of enhancer activity in each BLC lineages as well as in metastatic cell lines relative to non-metastatic cell lines. Our analysis in the T24 lineage revealed a striking feature, a dramatic loss of intronic and distal DHSs (DNase I Hypersensitive sites), during the initial transition to tumorigenic type. During metastatic progression, new enhancer classes emerged and there was an enrichment for association with target organ-specific genes. The analysis of differential DHSs between metastatic and non-metastatic BLCs identified an enhancer signature enriched with lost DHSs in metastatic BLCs where nearby genes were associated with cellular movement/invasion functions. Lost DHSs were also present near key factors such as PPARG, RXRA, FOXA1, TP63, and GATA3, which play a role in urothelial development and differentiation, and the transcription activity of those genes were correlated with the change of enhancer activity. This study identified a set of DHSs that are associated with cancer progression in bladder cancer, and provides a potential clinical application for developing prognostic markers to predict the risk of developing aggressive disease. Citation Format: Sohyoung Kim, Lyuba Varticovski, Qizong Lao, Songjoon Baek, Michael L. Nickerson, Myong-Hee Sung, Lars Grontved, Thompson Bethtrice, Dan Theodorescu, Piyush K. Agarwal, Michael Dean, Gordon Hager. Genome-wide enhancer identify signature predictive of metastatic phenotypes in bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3352. doi:10.1158/1538-7445.AM2017-3352
Abstract 1144: Dual inhibition of MEK1/2 and PLK1 specifically targets aggressive breast cancer cell population with CEP55 elevated expression
Authors: Debottam Sinha, Murugan Kalimutho, J. Alejandro Lopez, Kum Kum Khanna
Journal: Cancer Research (2017)

Abstract Triple negative breast cancers (TNBCs), lacking the expression of ER, PR and HER2 amplification, are the most aggressive form of breast cancer (BC). Due to their heterogeneity influenced by high level of genomic instability and aneuploidy, treatment of TNBC patients is one of the biggest challenges faced in the clinics. CEP55, discovered first by our laboratory, is a key regulator of cytokinesis malfunction of which has been shown to cause multinucleation. Furthermore, ERK2/PLK1 critically regulates the functional role of CEP55 via phosphorylation of CEP55 at particular stages of mitosis, allowing it to localize to the midbody for accurate cytokinesis. Research has demonstrated association of CEP55 with various cancers especially BC as over-expression of CEP55 mRNA is associated with worse BC prognosis and poor survival. We hypothesized that, CEP55 regulates the fate of aneuploid cell population, which are highly dependent on mitotic genes for tumor progression among aggressive BC, thus can be targeted for therapy development. We have performed a series of in vitro studies demonstrating that depletion of CEP55 sensitizes cells to anti-mitotic drugs like PLK1 inhibitor (BI2536) and leads to unscheduled CDK1/Cyclin B activation and favor CDK1-Caspase 3-dependent mitotic catastrophe. We also demonstrate that ERK1/2 transcriptionally controls CEP55 mRNA and due to lack of a specific small molecule inhibitor against CEP55, inhibition of MEK1/2 using the small molecule inhibitor Selumetinib, can mimic depletion of CEP55 in vivo. Thus, we rationalized the usage of a MEK1/2 inhibitor in combination with a PLK1 inhibitor across a series of BC cell lines. We observed synthetic lethality among the aggressive hormone receptor negative cell lines, which expressed higher expression of CEP55 compared to normal like and hormone receptor positive BC cell lines with lower CEP55 level. The combination synergistically increased apoptosis of aneuploid population via premature entry of these cells into mitosis in the presence of antimitotic drugs due to exhaustion of CEP55. We have also validated this synergistic effect of MEK1/2 and PLK1 inhibition using xenograft models, results of which imitated the in vitro findings. Therefore, we propose a novel treatment strategy of MEK1/2-PLK1 dual combination for selectively targeting CEP55 over-expressing BC in the clinics. Citation Format: Debottam Sinha, Murugan Kalimutho, J. Alejandro Lopez, Kum Kum Khanna. Dual inhibition of MEK1/2 and PLK1 specifically targets aggressive breast cancer cell population with CEP55 elevated expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1144. doi:10.1158/1538-7445.AM2017-1144
Abstract 5363: Measuring gene expression at the tumor microenvironment: A comparison between nCounter PanCancer Immune Profiling Panel and Oncomine Immune Response Research Assay
Authors: Ann Mongan, Warren Tom, Janice Au-Young, Aleksandr Pankov, Gauri Ganpule, Fiona Hyland
Journal: Cancer Research (2017)

Abstract The tumor microenvironment, especially infiltrating T lymphocytes and inflammatory molecules, is believed to be highly relevant to the tumor’s sensitivity to cancer checkpoint blockade therapy. At the same time, the exact markers that are predictive of response for each therapeutic agent are still the subject of active investigations. To address the need for better understanding of the effect of different T cell subsets, antigen presentation, and tumor killing, gene expression profiling presents an attractive means to simultaneously evaluate the tumor microenvironment and cancer cells. In this study we compare the results and performance of the nCounter PanCancer Immune Profiling Panel and the Oncomine Immune Response Research Assay, both of which are designed to measure the expression of genes indicative of an immune response and potential immune-editing activities by tumor cells. The nCounter panel detects gene expression by counting unique probes that hybridize target mRNA, while the Oncomine panel employs NGS to sequence and count reads derived from the targets. While both panels are designed to work with FFPE samples, The nCounter panel expects 100 ng of unamplified RNA, while the Oncomine panel requires only 10 ng total RNA with its AmpliSeq technology. The two panels share 254 common genes, which constitute the basis for this comparison. Across 12 cancer samples (breast, H&amp;N, melanoma, NSCLC, and RCC), results show that the Oncomine panel offers 20% higher dynamic range, thereby providing more robust readouts about the differences among samples. More importantly, with virtually no background noise, the underlying NGS technology provides an absolute zero readout for non-expressing genes which significantly improves the sensitivity for detecting low expressing genes, as their presence can be confirmed by as few as two reads. The two technologies show moderate correlation (R ~ 0.7), with the Oncomine panel more strongly correlating with qPCR (R ~ 0.9). Finally, when clustered using all genes on the panel, only the Oncomine panel provides clear stratification of cancer types, thus allowing the panel to be used for tissue type confirmation in addition to evaluating the immune response. Citation Format: Ann Mongan, Warren Tom, Janice Au-Young, Aleksandr Pankov, Gauri Ganpule, Fiona Hyland. Measuring gene expression at the tumor microenvironment: A comparison between nCounter PanCancer Immune Profiling Panel and Oncomine Immune Response Research Assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5363. doi:10.1158/1538-7445.AM2017-5363
Abstract 5492: Comprehensive analysis of the dynamics of aberrant WNT signaling on global gene expression and nuclear structure
Authors: Markus A. Brown
Journal: Cancer Research (2017)

Abstract The organization of the genome in the nucleus is complex and dynamic. Features of the nuclear architecture, including the spatial arrangement of genomic sequences, the structure of chromatin, and the accessibility of regulatory DNA elements modulate nuclear processes such as gene transcription DNA replication, DNA repair, RNA processing, and mRNA transport. However, the interplay between nuclear architecture and gene expression is poorly understood. We propose to elucidate the impact of silencing the prominent transcription factor, TCF7L2, the major effector of the WNT signaling pathway, on the transcriptional equilibrium and nuclear architecture of the nucleus in human colorectal cancer cells. Our multidisciplinary approach combines targeted silencing of TCF7L2, 3D-FISH, RNA-seq, and Hi-C chromosome conformation capture, in parallel with mathematical modeling to delineate structure/function relationships in the interphase nucleus. This approach will elucidate the intricacies of a dynamic cellular signaling pathway in three-dimensional space. Citation Format: Markus A. Brown. Comprehensive analysis of the dynamics of aberrant WNT signaling on global gene expression and nuclear structure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5492. doi:10.1158/1538-7445.AM2017-5492
Health and Spirituality
Authors: Tyler J. VanderWeele, Tracy A. Balboni, Howard K. Koh
Journal: JAMA (2017)

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Abstract 5704: Ultrasensitive mutational analysis in cell-freeDNA by targeted next-generation sequencing with molecular tags
Authors: Nga Wan Rachel Tam, Irmina Diala, Xiaoji Chen, Walter Darbonne
Journal: Cancer Research (2017)

Abstract Circulating cell-free DNA (cfDNA) in plasma offers a non-invasive approach to monitor tumor molecular profiling in real-time at multiple time-points, detection of emerging genomic alterations associated with drug resistance and clarifying cancer prognosis and diagnosis of cancer recurrence or progression. Therefore, it is crucial to improve our current NGS technology to detect low frequency alleles in cfDNA. There are many technical challenges in NGS technology, including base errors generated from library preparation and sequencing, making it hard to distinguish real mutations from false positives produced from amplification sequencing and base-calling processes. We have adopted a more sensitive approach to overcome this challenge. We used short, random DNA sequences called unique molecular tags (UMTs) during library preparation to label input DNA. This technique can remove background errors, false positives during data analysis, providing high confident mutation calls with better sensitivity down to 0.1% (depends on DNA input amount). We will present data showing validation of this NGS platform using commercially available DNA control, archival FFPE tissue and cfDNA matched samples and demonstrate robust sensitivity and specificity by using the off-the-shelf Archer Reveal ctDNA panel for Illumina covers 28 oncogenes. This molecular-tagged NGS panel can detect mutations down to 0.1% allelic frequency. This robust NGS platform is being used in our lab to analyze cfDNA samples, enabling the development of a non-invasive method to overcome existing challenges to provide molecular understanding of patient’s tumor evolution in real time, and aid in the development of personalized therapies for cancer patients. Citation Format: Nga Wan Rachel Tam, Irmina Diala, Xiaoji Chen, Walter Darbonne. Ultrasensitive mutational analysis in cell-freeDNA by targeted next-generation sequencing with molecular tags [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5704. doi:10.1158/1538-7445.AM2017-5704