bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A45: Semaphorin 3C mediates glioma stem cell tumorigenicity and radioresistance
Authors: Yu Jennifer , Man Jianghong , Jocelyn Shoemake , Qiulian Wu , Rich Jeremy , Bao Shideng 
Published: May 2016

Abstract
Purpose: Different cancer cell compartments often communicate through soluble factors to facilitate tumor growth. Glioma stem cells (GSCs) are a subset of tumor cells that resist standard therapy to contribute to disease progression. How GSCs employ a distinct secretory program to communicate with and nurture each other over the non-stem tumor cell (NSTC) population is not well defined.
Methods/Materials: GSCs were enriched from patient specimens and functionally validated. We used a candidate approach to screen for secreted factors that were preferentially used by GSCs but not NSTCs. Expression was assessed by Western blot, and confirmed by immunohistochemistry and immunofluorescence in vitro and in human and mouse GBM tissues. Ligand-receptor interactions were confirmed by co-immunoprecipitation. Rac activity was assessed by Rac-GTP pulldown. Co-culture epistasis experiments were performed using knockdown and recombinant protein approaches. Glioma stem cell marker analysis (CD133, Sox2, Olig2), cell viability (ATP-dependent assays), apoptosis (TUNEL, PI/AnnexinV, cleaved caspase 3/7), self-renewal (tumorsphere formation and limiting dilution assay) and invasion (transwell migration assay) were performed. GSCs were separated in PlexinD1 hi and lo populations by FACS. Radiation (3 Gy) was delivered by Cs-137 irradiator. GSCs were used to establish orthotopic xenograft models of glioblastoma and tumor growth and animal survival were assessed.
Results: We have found that GSCs preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate Rac1/NFkB signaling in an autocrine and paracrine loop to promote their own survival. Importantly, Sema3C is not expressed in neural progenitor cells (NPCs) or NSTCs. Disruption of Sema3C induced apoptosis of GSCs, but not NPCs or NSTCs, and suppressed tumor growth in orthotopic models of glioblastoma. Introduction of activated Rac1 rescued the Sema3C knockdown phenotype in vivo. Furthermore, GSCs that expressed high levels of PlexinD1 receptors were more resistant to radiation, and Sema3C and PlexinD1 were upregulated after irradiation. Together, these data support that Sema3C signaling contributes to radiation resistance.
Conclusions: Our study supports targeting Sema3C to break this GSC-specific autocrine/paracrine loop to improve glioblastoma treatment, potentially with a high therapeutic index.
Citation Format: Jennifer Yu, Jianghong Man, Shoemake Jocelyn, Wu Qiulian, Jeremy Rich, Shideng Bao. Semaphorin 3C mediates glioma stem cell tumorigenicity and radioresistance. [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 A45.
Abstract B01: Molecular evolutionary process of malignant glioma
Authors: Galvao Rui P. , Bassham Susan , Nelson Thomas C. , Sydes Jason , Rosenfeld Lauren K. , Cresko William A. , Zong Hui 
Published: May 2016

Abstract
Malignant gliomas are devastating, incurable brain tumors, with a bleak prognosis that improved little over the past decades. Many studies have been published describing genomic and transcriptomic alterations in malignant, fully formed gliomas. However, little is known of what takes place before the malignant stage, even though transformation of a normal cell into cancer is a multi-step process and, by the malignant stage, tumor cells have become very different from their original, untransformed ancestry. To gain insight into the driving forces of glioma and develop effective treatments, one must understand the entire process of tumorigenesis, for which it will be necessary to directly characterize the cell of origin of glioma at multiple time points throughout gliomagenesis.
We recently identified adult oligodendrocyte precursor cells (OPCs) as a cell of origin for malignant gliomas using a genetic mouse model that induces mutations in p53 and NF1, two of the most frequently mutated genes in human glioblastoma [Galvao et al., 2014, PNAS]. To ensure the introduction of mutations into adult but not neonatal OPCs, we used NG2-CreER that can specifically induce loxP-mediated recombination upon the administration of tamoxifen. Time course analysis revealed several distinct stages of gliomagenesis, starting with a rapid but transient hyper-proliferation shortly after tamoxifen administration, followed by a long dormancy period and ending with malignant transformation.
To further investigate the molecular changes during the pre-transforming stages, using the same mouse model, we developed a procedure based on laser capture microdissection to collect OPCs from the adult brain at distinct stages during gliomagenesis. We then used RNA sequencing to gain mechanistic insight into the successive stages of gliomagenesis. Our results show that, compared to tumor OPCs, the gene expression profile of pre-transforming mutant OPCs remains similar to that of wild-type OPCs, indicating that most transcriptional changes occur at the final transformation step. Interestingly, careful analysis revealed expression changes in hundreds of genes shortly after p53/NF1 mutagenesis. Using bioinformatics tools such as Gene Ontology (GO) terms, Gene Set Enrichment Analysis (GSEA) and Signaling Pathway Impact Analysis (SPIA), we are currently identifying the signaling pathways most affected at each time point to gain a better understanding of the molecular evolution from mutant OPCs to malignant glioma, which could provide critical insights on how to halt or even revert that process.
Citation Format: Rui P. Galvao, Susan Bassham, Thomas C. Nelson, Jason Sydes, Lauren K. Rosenfeld, William A. Cresko, Hui Zong. Molecular evolutionary process of malignant glioma. [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 B01.
Abstract B11: The oncogenic role of I2PP2A by inhibiting NME1 in SHH medulloblastoma
Authors: Wei Yun , Kenney Anna Maria 
Published: May 2016

Abstract
Medulloblastoma is a pediatric brain tumor which arises in the cerebellum and is the most common childhood malignancy. The current standard of treatment for medulloblastoma (MB) is a combination of surgery, radiation and chemotherapy, which can cause lifelong side effects to MB survivors due to damage to the developing brain. Approximately 30% of human MB show aberrant Sonic Hedgehog (SHH) signaling and feature mutated SMO/PTCH1 or amplified GLI/NMYC, components of the SHH pathway. To study SHH-driven mitogenic and oncogenic signaling pathways, we use the NeuroD2-SmoA1 mouse model to investigate how downstream effectors of SHH signaling regulate cell proliferation in MB development. The NeuroD2-SmoA1 mouse closely recapitulates human SHH MB and bears constitutively active SMO in its cerebellum. The early onset and high incidence of tumors, and the adherence to human pathology make NeuroD2-SmoA1 mouse an efficient model for MB research. Utilizing this model, I have been focusing on the nuclear oncoprotein, I2PP2A, also known as endogenous inhibitor 2 of phosphatase 2A. I2PP2A has recently been proposed to be targeted in other malignant tumors such as leukemia, prostate, and lung cancers. However, whether I2PP2A play oncogenic roles in medulloblastoma has not been established yet. I found that I2PP2A protein is markedly elevated in mouse MB cytosol compared with neighboring normal cerebellum through histology and western blot approaches. In the efforts of searching molecules interacting with I2PP2A in cytoplasm, a non-metastasis marker, called NME1, stands out as the cytosol level of this protein also shows a strong induction. NME1 is a DNase that triggers cell death when tumor cells encounter the immune attack from the microenvironment. Based on the preliminary data, I hypothesize that I2PP2A sequesters NME1 in cytosol and inhibits the activation of this DNA nicking protein, thus prevents the MB cell death. My future plans are to determine the roles of I2PP2A and NME1 in tumorigenesis, test whether inhibiting I2PP2A can induce MB cell death mediated by NME1, and finally extrapolate this research to novel therapy design targeting I2PP2A in SHH medulloblastoma.
Citation Format: Yun Wei, Anna Maria Kenney. The oncogenic role of I2PP2A by inhibiting NME1 in SHH 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 B11.
Abstract B20: Targeting Olig2 co-regulators for malignant glioma therapy
Authors: Kupp Robert , Cascio Costanza Lo , Rauf Femina , Meijer Dimphna , Stiles Charles D. , Sanai Nader , LaBaer Joshua , Mehta Shwetal V. 
Published: May 2016

Abstract
The transcription factor OLIG2 is expressed within the highly tumorigenic sub-population of stem-like cells in malignant glioma and required for tumor formation in orthotopic grafts of human glioma as well as genetically defined murine glioma models. Our work (recently confirmed and extended by Suva et al., 2014) suggests that small molecule OLIG2 antagonist could serve as targeted therapy for high grade gliomas – either as a mono therapeutic or as an adjuvant to conventional radiotherapy or cytotoxic drugs. However, transcription factors in general are considered to be unattractive targets for drug development because their interactions with DNA and co-regulatory proteins involve large and complex surface area contacts. Our recent data suggests that OLIG2 interacts with distinct partner proteins based on its phosphorylation state, which in turn regulates its pro-mitogenic functions. Here we employed two independent proteomics screens (mass spectrometry and Nucleic Acid Programmable Protein Arrays, NAPPA) to identify OLIG2 co-regulators as possible surrogate targets to suppress OLIG2 function. These screens led to identification of two novel OLIG2 partner proteins: HDAC1 and proto-oncogene FYN kinase. OLIG2 is known to be a negative regulator of gene expression and histone deacetylation is required for suppression of gene expression. We demonstrate that OLIG2 functions as an HDAC1 carrier, delivering this enzyme to specific target genes (e.g., p21) and non-histone proteins like p53. HDACs are ubiquitously expressed and are known to be redundant, but we show that ablation of HDAC1 alone (using shRNA) significantly decreases the proliferation of glioma initiating cells with minimal impact on normal neural stem cells. In addition, we show that FYN kinase interacts with OLIG2 and phosphorylates it at tyrosine residues. Ablation of FYN decreases phosphorylation of OLIG2 at tyrosine residues and affects OLIG2-mediated expression of oncogenic target genes like EGFR and WNT5a. This work provides two potential co-regulators of OLIG2 which could serve as druggable surrogate targets to block OLIG2 function in malignant glioma. Further work will evaluate the efficacy of HDAC1 and FYN-specific inhibitor as single agents or as adjuvant therapy to radiation and temozolomide in orthotopic patient-derived xenograft models. Targeting factors regulating OLIG2-mediated tumor growth will have practical overtones for targeted therapies for malignant gliomas.
Citation Format: Robert Kupp, Costanza Lo Cascio, Femina Rauf, Dimphna Meijer, Charles D. Stiles, Nader Sanai, Joshua LaBaer, Shwetal V. Mehta. Targeting Olig2 co-regulators for malignant glioma therapy. [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 B20.
Abstract IA02: Molecular pathogenesis of IDH mutant cancers and evolving treatment strategies
Authors: Kaelin William G. 
Published: May 2016

Abstract
IDH1 and IDH2 mutations have now been described in a variety of cancers including gliomas, acute myelogenous leukemias, chondrosarcomas, cholangiocarcinomas, and angioimmunoblastic T-cell lymphoma. Tumor-associated IDH1 and IDH2 mutants produce large amounts of the R enantiomer of 2-hydroxyglutarate (R-2HG), which accumulates to mM levels in IDH mutant tumor cells. R-2HG modulates (usually inhibits) various 2-oxoglutarate-dependent enzymes, including various 2-oxoglutarate-dependent dioxygenases. Examples of such dioxygenases include the JmjC family of histone demethylases and the TET methylcytosine hydroxylases. The challenge for the field has been to determine which enzymes, when modulated by R-2HG, drive transformation and which are simply bystanders. We developed a cell-based assay for hematopoietic transformation by mutant IDH and showed that transformation in this setting is indeed mediated by R-2HG and that its effects are reversible. Moreover, we and others provided evidence that inhibition of TET2 by R-2HG contributes to leukemic transformation in cells carrying IDH mutations. Small molecules that block R-2HG production appear promising based on early Phase 1 data in IDH1 and IDH2 mutant leukemias. We also developed a model of astrocytic transformation by IDH. We found that activation of the EglN prolyl hydroxylases, which target the HIF transcription factor for destruction, by R-2HG promotes soft agar growth by immortalized astrocytes but is not sufficient to promote tumor growth in immunocompromised mice. More recently we have developed an oncogene cooperation assay in which mutant IDH promotes tumor growth in mice. In addition, we have identified an enzyme in glioma cells that, when inhibited by R-2HG, creates a distinctive metabolic profile and renders IDH mutant cells dependent on glutaminase activity for survival.
Citation Format: William G. Kaelin, Jr. Molecular pathogenesis of IDH mutant cancers and evolving treatment strategies. [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 IA02.
Abstract IA23: Medulloblastoma subgroup-specific mutations model the tumor microenvironment
Authors: Gilbertson Richard J. 
Published: May 2016

Abstract
Brain tumors, especially those arising in children, are remarkably heterogeneous in their response to treatment. Understanding the processes that dictate treatment sensitivity is important if we are to cure all patients. Most research has focused on identifying tumor cell intrinsic properties that regulate treatment response; but the role of the tumor microenvironment is less well understood. Here, we show that distinct subtypes of medulloblastoma possess markedly different vasculatures that are determined non-autonomously by tumor genotype, and that dictate response to systemic chemotherapy. We found that WNT-antagonists secreted by WNT-medulloblastoma – an essentially curable form of the disease – silence WNT signaling in neighboring endothelial cells, causing the formation of fenestrated and highly permeable vessels normally associated with peripheral organs: endothelial WNT signaling is essential to form and maintain the blood brain barrier (BBB). Consequently, systemically delivered chemotherapy accumulated to high levels in WNT-medulloblastomas, eliciting a marked clinical response. In contrast, while cells derived from Sonic Hedgehog (SHH)-medulloblastoma – a much less curable subtype – were intrinsically chemosenstive, they did not secrete WNT-antagonists, formed tumors with an intact, chemo-impermeable BBB and were chemoresistant in vivo. Remarkably, reactivation of WNT-signaling in WNT-medulloblastoma endothelial cells restored BBB function, rendering these tumors chemoresistant. Our data provide direct evidence that brain tumor genotype can dictate tumor vessel phenotype in a non-autonomous fashion, providing a potential explanation for the excellent prognosis of WNT-medulloblastoma. Pharmacological inhibition of endothelial WNT signaling in other primary and secondary brain tumors might enhance chemoresponsiveness by disrupting the BBB.
Citation Format: Richard J. Gilbertson. Medulloblastoma subgroup-specific mutations model the tumor microenvironment. [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 IA23.
Abstract A33: Mediator is an intrinsically dynamic complex critical to Hsf1-activated transcription
Authors: Anandhakumar Jayamani , Moustafa Yara , Chowdhary Surabhi , Kainth Amoldeep S. , Gross David S. 
Published: May 2016

Abstract
Mediator is an evolutionarily conserved transcriptional coactivator that plays a vital role in the regulation of RNA polymerase II (Pol II) transcribed genes in eukaryotes as diverse as yeast and human. It consists of a tri-modular core complex comprised of Head, Middle and Tail modules and a dissociable Cdk8/Kinase module (CKM). Although it has been assumed that core Mediator in the model eukaryote S. cerevisiae (budding yeast) exists as a stable 21-subunit complex based on cell-free assays, its structural state in vivo is unclear. We have obtained evidence that the Tail module is highly dynamic, and that a subcomplex consisting of Tail subunits Med2, Med3 and Med15 can be independently recruited to the UAS/promoter regions of Heat Shock Factor 1 (Hsf1)-regulated genes in response to acute thermal stress. Med2-Med3-Med15 autonomy is revealed by ChIP analysis following the “anchoring away” of select Mediator core subunits located in either Middle or Tail module. Such conditional depletion leads to a 60-80% reduction in HSP gene transcription. We additionally observed that Hsf1 can recruit the CKM independently of the core complex, and that both core Mediator and CKM recruitment occurs independently of SAGA. Collectively, our results indicate that yeast Mediator is intrinsically dynamic and that multiple species, including CKM-Mediator, the 21-subunit core complex, the Med2-Med3-Med15 Tail Triad and the four-subunit CKM, can be independently recruited by Hsf1 to its target genes.
Citation Format: Jayamani Anandhakumar, Yara Moustafa, Surabhi Chowdhary, Amoldeep S. Kainth, David S. Gross. Mediator is an intrinsically dynamic complex critical to Hsf1-activated transcription. [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 A33.
Abstract B10: Increased expression of EZH2 and TOP2A predicts for a poorer prognostic outcome in Genitourinary Cancers
Authors: Rosario Spencer , Dalimov Zafardjan , Kirk Jason , Morrell Kayla , Eng Kevin , Ellis Leigh 
Published: May 2016

Abstract
The enhancer of Zeste homolog 2 (EZH2), a component of the Polycomb Repressive Complex 2 (PRC2), is an epigenetic silencer that is known to be highly expressed in both metastatic and primary prostate cancer (PCa). More recently, topoisomerase IIα (TOP2A), an enzyme that controls the topologic states of DNA during the cell cycle, has also been identified as being highly expressed in PCa. Both EZH2 and TOP2A have been associated with more aggressive disease and poorer prognostic outcome. During genome-wide analysis, using The Cancer Genome Atlas (TCGA), EZH2 and Top2A were found to be highly positively correlated, most noticeably in PCa and clear cell Renal Cell Carcinoma (ccRCC). As a result, we predicted increased expression of both EZH2 and TOP2A in an individual, would predict for a worse prognostic outcome than either gene being highly expressed alone. Further analysis of the TCGA and Memorial Sloan Kettering Cancer Center (MSKCC) datasets, demonstrated that increased expression of these two genes predicted for a poorer prognostic outcome in genitourinary cancers. In tumor samples with increased expression of EZH2 and TOP2A, as compared to the tumor samples that did not concurrently overexpress both EZH2 and TOP2A, patients displayed worse overall Regression Free Survival (RFS), which were associated with increase hazard ratio, and tumor staging and grades. . As these poor prognostic markers were consistent across multiple cancer subtypes, we are beginning to explore those genes that are differentially expressed in individuals with concurrent high TOP2A and EZH2 as a means of further characterizing this novel phenotype. Since these two genes are targetable by drugs such as etoposide (a TOP2 poison) and DZNep (an EZH2 inhibitor), it makes them attractive candidates for treatment in those individuals who not only have tumors that highly express these two genes, but also those individuals that have exacerbated existing treatment options.
Citation Format: Spencer Rosario, Zafardjan Dalimov, Jason Kirk, Kayla Morrell, Kevin Eng, Leigh Ellis. Increased expression of EZH2 and TOP2A predicts for a poorer prognostic outcome in Genitourinary Cancers. [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 B10.
Abstract B14: Use of DNA methylation in circulating free DNA as a potent biomarker for pancreatic cancer detection
Authors: Shinjo Keiko , Kondo Yutaka 
Published: May 2016

Abstract
Pancreatic cancer is highly lethal malignancy despite the recent clinical advancement. Since pancreatic cancer is often difficult to diagnose, there is an urgent need to develop novel biomarkers for early detection with blood tests. Epigenetic alterations have emerged as a common hallmark of many types of human cancers as well as pancreatic cancer. Studies have shown that epigenetic dysregulation is associated with multiple steps during carcinogenesis. Therefore, invention of blood-based DNA methylation biomarkers and their high-sensitive detection system may be a promising diagnostic tool for pancreatic cancer. In order to establish the diagnostic system, first, we performed genome-wide DNA methylation analysis of 38 EUS-FNA specimens of pancreatic cancer with clinical stage III-IV using Illumina Infinium HumanMethylation450 BeadChip. We further analyzed the DNA methylation profiles of other types of tumors in the public database, TCGA (The Cancer Genome Atlas), and identified five marker genes, which were specifically methylated in pancreatic cancers. In addition, analysis of DNA methylation status of pancreas cancers comparing 10 normal tissues in TCGA data set revealed that 99% of tumors were methylated at least one of the five markers (sensitivity, 98.9%; specificity, 44%). We next examined the DNA methylation status in the markers in the validation cohort (n=19) by bisulfite pyrosequencing and quantitative methylation specific PCR and found that 18/19 (95%) cases were methylated in at least one marker (AUC=0.95). Currently, our preliminary data showed that more than 95% of cancer patients have aberrant DNA methylation in circulating free DNA (cfDNA). Our results indicate that detection of DNA methylation in the cfDNA might be a promising and potent tool for diagnosis of pancreatic cancers.
Citation Format: Keiko Shinjo, Yutaka Kondo. Use of DNA methylation in circulating free DNA as a potent biomarker for pancreatic cancer detection. [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 B14.