bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-063: PTEN function is controlled by recruitment to cytoplasmic vesicles
Authors: Naguib Adam , Bencze Gylua , Cho Hyejin , Zheng Wu , Tocilj Ante , Elkayam Elad , Faehnle Christopher R , Jaber Nadia , Pratt Christopher , Chen Muhan , Zong Wei-Xing , Marks Michael S , Joshua-Tor Leemor , Pappin Darryl J , Trotman Lloyd C. 
Published: August 2015

Abstract
PTEN is thought to function at the plasma membrane where receptor tyrosine kinases activate PI 3-Kinases. Yet the majority of PTEN is located throughout the cytoplasm so that only a fraction of PTEN could be actively suppressing PI 3-K signaling at any time. Here we show that cytoplasmic PTEN is distributed along microtubules, tethered to vesicles via interaction with phosphatidylinositol 3- phosphate (PI(3)P), the signature lipid of endosomes. We demonstrate that the C2 domain of PTEN specifically binds PI(3)P via the CBR3-loop. Mutations that render the CBR3-loop incapable of PI(3)P binding abrogate PTEN function in cells but not in vitro. The loss-of-function in cells is rescued by fusion of the canonical PI(3)P vesicle targeting domain, FYVE, to CBR3-loop mutant PTEN, demonstrating the functional relevance of PTEN activity on endosomal membranes. These findings introduce an entirely unexpected site of action of the PTEN tumor suppressor. Furthermore, they introduce the concept of PI 3-K signal activation over the vast surface of the plasma membrane that is contrasted by PTEN-mediated signal termination on the discretely sized and much smaller surfaces of endocytic vesicles. Implications of these results for cancer signaling and growth control will be discussed.
Note: This abstract was not presented at the meeting.
Citation Format: Adam Naguib, Gylua Bencze, Hyejin Cho, Wu Zheng, Ante Tocilj, Elad Elkayam, Christopher R Faehnle, Nadia Jaber, Christopher Pratt, Muhan Chen, Wei-Xing Zong, Michael S Marks, Leemor Joshua-Tor, Darryl J Pappin, Lloyd C. Trotman. PTEN function is controlled by recruitment to cytoplasmic vesicles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-063. doi:10.1158/1538-7445.AM2015-LB-063
Abstract LB-065: Mutational and functional analysis of the tumor suppressor PTPRD in human melanoma
Authors: Walia Vijay , Prickett Todd , Kim Jung-Sik , Gartner Jared J. , Lin Jimmy C. , Rosenberg Steven A. , Elble Randolph C. , Solomon David A. , Waldman Todd , Samuels Yardena 
Published: August 2015

Abstract
Protein tyrosine phosphatases (PTPs) tightly regulate tyrosine phosphorylation essential for cell growth, adhesion, migration, and survival. We performed a mutational analysis of the PTP gene family in cutaneous metastatic melanoma and identified 23 phosphatase genes harboring somatic mutations. Among these, receptor-type tyrosine-protein phosphatase delta (PTPRD) is one of the most highly mutated genes, harboring 17 somatic mutations in 79 samples, a prevalence of 21.5%. Functional evaluation of six PTPRD mutations show enhanced anchorage-dependent and anchorage-independent growth. Interestingly, melanoma cells expressing mutant PTPRD are significantly more migratory than cells expressing wild-type PTPRD or vector alone, indicating a novel gain-of-function associated with mutant PTPRD. To understand the molecular mechanism of PTPRD, we searched for its binding partners by converting the active PTPRD enzyme into a ‘‘substrate trap’’ form. Using mass spectrometry and co-immunoprecipitation, we report desmoplakin, a desmosomal protein that is implicated in cell-cell adhesion, as a novel PTPRD substrate. Further analysis showed reduced phosphatase activity of mutant PTPRD against desmoplakin. Thus our study has established a novel link between PTPRD and desmoplakin and identified a phosphatase implicated in desmosome formation, which is disrupted in melanoma. As both Met and EGFR signaling have been shown to be involved in desmoplakin phosphorylation and their respective inhibitors, SU11274 and Gefinitib reduce its phosphorylation; melanoma cells harboring PTPRD mutations may be selectively sensitive to these two inhibitors. Moreover, because PTPRD is also mutated in glioblastomas and adenocarcinoma of the colon and lung, our data might be applicable to a number of human cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Vijay Walia, Todd Prickett, Jung-Sik Kim, Jared J. Gartner, Jimmy C. Lin, Steven A. Rosenberg, Randolph C. Elble, David A. Solomon, Todd Waldman, Yardena Samuels. Mutational and functional analysis of the tumor suppressor PTPRD in human melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-065. doi:10.1158/1538-7445.AM2015-LB-065
Abstract LB-078: RNAi and CRISPR/Cas9-based in vivo models for drug discovery
Authors: Premsrirut Prem K. , Fellmann Christof 
Published: August 2015

Abstract
Genetically engineered mouse models (GEMMs) are a powerful platform that enable the study of disease initiation and maintenance, the microenvironment and the responsiveness of disease to known or novel therapeutics; however, the long lead times and high costs required to develop, intercross and maintain models with various disease predisposing gene combinations have limited their practical utility in the drug discovery process. RNA interference (RNAi), a mechanism that controls gene expression, is a rapid and cost-effective alternative to gene deletion that can be exploited experimentally to reversibly silence nearly any gene target not only in vitro but also in live mice. By using our “Sensor assay” to biologically identify short hairpin RNAs (shRNAs) that induce potent gene suppression in combination with a new miRNA scaffold, miR-E, we have engineered a reliable system for in vivo gene suppression. Furthermore, by utilizing tetracycline-regulated miR-E based shRNAs with high efficiency ES cell targeting, we have developed a fast, scalable pipeline for the production of shRNA transgenic mice with reversible gene silencing. Recently, with the advent of new genome editing techniques, such as CRISPR/Cas9 technology, we are able to introduce additional sensitizing lesions to induce disease pathogenesis. In synergy with RNAi technology, complex multi-allelic ESC based GEMMs can be generated without extensive intercrossing. Using this combination of CRISPR/Cas9 and RNAi technologies, we are able to not only model disease pathogenesis, but also mimic drug therapy in mice, giving us unprecedented capabilities to perform preclinical studies in vivo. Here, we demonstrate that RNAi in combination with CRISPR/Cas9 genome editing enables us to recapitulate the phenotypes of knockout mice and further explore potential therapeutic approaches within the same model. Using our robust system, we have created a a cost-effective and scalable platform for the production of complex GEMMs with RNAi silencing of nearly any gene - mice with enormous predictive power that will shape our development of better tolerated therapies.
Citation Format: Prem K. Premsrirut, Christof Fellmann. RNAi and CRISPR/Cas9-based in vivo models for drug discovery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-078. doi:10.1158/1538-7445.AM2015-LB-078
Abstract LB-079: Specific epigenetic reader role for cyclin D1
Authors: Di Sante Gabriele , Casimiro Mathew Craig , Wang Chenguang , Yu Zuoren , Crosariol Marco , Vadlamudi Ratna K. , Mann Monica , Tompa Peter , Tantos Agnes , Pestell Richard G. 
Published: August 2015

Abstract
Amplification of the CCND1 gene occurs in approximately 30% of human breast cancer and is sufficient when overexpressed for the induction of mammary tumorigenesis. A DNA-associated form of cyclin D1 governs gene expression and chromosomal instability. Herein, the mechanisms governing gene activation by cyclin D1 were defined. Cyclin D1 was recruited to activate gene regulatory regions associated with enrichment of p300, HP1α and reduced HDAC3 and SUV39H1. The recruitment of cyclin D1 into local chromatin was dissociable from its kinase function and required an intrinsically disordered carboxyl-terminus flanked by a glutamine-rich motif. The cyclin D1 epigenetic interaction motif bound acetylated or methylated H3 on specific residues (H3K36me2, H3K9me3). Cyclin D1 bound to the Top2A gene promoter induced Top2A transcription, abundance and sensitivity to Top2A inhibitors. The direct recognition of an epigenetic code by a motif within cyclin D1 and the induction of Top2A may facilitate communication of genome wide expression changes during cell-cycle progression and tumorigenesis.
Citation Format: Gabriele Di Sante, Mathew Craig Casimiro, Chenguang Wang, Zuoren Yu, Marco Crosariol, Ratna K. Vadlamudi, Monica Mann, Peter Tompa, Agnes Tantos, Richard G. Pestell. Specific epigenetic reader role for cyclin D1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-079. doi:10.1158/1538-7445.AM2015-LB-079
Abstract LB-093: Activation of the FGFR1 signaling pathway by the epstein-barr virus-encoded LMP1 promotes aerobic glycolysis and transformation of human nasopharyngeal epithelial cells
Authors: Lo Kwok Fung , Dawson Christopher W , Young Lawrence S , Lo Kwok Wai 
Published: August 2015

Abstract
Undifferentiated nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) latent infection. The EBV-encoded latent membrane protein 1 (LMP1) oncogene is believed to be important in NPC pathogenesis by virtue of its ability to activate multiple cell signaling pathways to induce proliferation, transformation, angiogenesis and invasiveness as well as modulation of energy metabolism. In this study, we report that LMP1 increases cell uptake of glucose and glutamine, enhances LDHA activity and lactate production, but reduces pyruvate kinase activity and pyruvate concentration. LMP1 also increases the phosphorylation of PKM2, LDHA and FGFR1 as well as expression of PDHK1, FGFR1, c-Myc and HIF-1α regardless of oxygen availability. This suggests that LMP1 promotes aerobic glycolysis. In addition to FGFR1, LMP1 also upregulates FGF2, the FGFR1 ligand, setting up a constitutive activation loop of FGFR1 signaling to promote aerobic glycolysis. FGFR1 inhibitors also abolish LMP1-mediated cellular transformation (proliferation and anchorage-independent growth) as well as cell migration and invasion in nasopharyngeal epithelial cells. Immunohistochemical staining revealed that a high level of phosphorylated FGFR1 is common in primary NPC specimens, and that this correlated with the expression of LMP1. Inhibition of FGFR1 activity in NPC cells results in the suppression of cell proliferation and anchorage-independent growth. Our current findings demonstrate that LMP1-mediated FGFR1 activation contributes to growth and transformation of epithelial cells, thereby implicating FGF2/FGFR1 signaling activation in the EBV-driven pathogenesis of NPC.
Citation Format: Kwok Fung Lo, Christopher W Dawson, Lawrence S Young, Kwok Wai Lo. Activation of the FGFR1 signaling pathway by the epstein-barr virus-encoded LMP1 promotes aerobic glycolysis and transformation of human nasopharyngeal epithelial cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-093. doi:10.1158/1538-7445.AM2015-LB-093
Abstract LB-100: Development of novel selective tumor-associated carbonic anhydrase inhibitors as promising anticancer agents
Authors: Alafeefy Ahmed Mahmoud , Atia Sabry , Ahmad Sheikh , Zoheir Khairy , Ashour Abdelkader , Kumar Ashok 
Published: August 2015

Abstract
The molecular complexity of cancers and therapy-related side effects often limit efficacy of numerous anti-tumor therapies, and warrant development of new drugs that are specific for certain molecular targets while minimizing the off-target effects. We previously have synthesized a series of benzene-sulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogues), and investigated such new compounds as inhibitors of the metalloenzyme carbonic anhydrase (CA). Specifically, we determined the inhibitory activity of such novel compounds against the cytosolic, house-keeping human (h) isoforms hCA I and II, as well as the transmembrane, tumor-associated ones CA IX and XII. Four compounds, namely CS2, CS6, CS8 and CS13, were very potent CA IX/XII inhibitors whereas they were much less effective as inhibitors of CA I and II. To determine whether these selective tumor-associated CA inhibitors exert antitumor activity, we examined their antiproliferative activity against the human medulloblastoma Daoy cell line, human hepatoma HepG2 cell line and the human epithelial cervical cancer Hela cell line. Compounds CS6 and CS13 showed significant antiproliferative activity against the three cancer cell lines. Daoy was the most sensitive cell line, and compound CS6 was the most potent one. Remarkably, compound CS6 was more potent against Daoy cells than the multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, dasatinib, since the former exerted smaller IC50 than that exerted by the latter (4.14 versus 7.28 μg/mL). In addition, flow cytometric Annexin-V/propidium iodide assay results showed that cell death induced by compounds CS6 is mediated, at least in part, by apoptosis. Moreover, CS6 significantly inhibited tyrosine kinase activity in Daoy cells, compared to DMSO-treated (control) cells. Taken together, these data indicate that compound CS6 is a novel multiple cancer pathways inhibitor, and warrants further investigation of its antitumor activity in medulloblastoma and other brain tumors. Currently, compounds CS6 and CS13 are being tested for their inhibitory activity against dihydrofolate reductase and thymidylate synthase.
Citation Format: Ahmed Mahmoud Alafeefy, Sabry Atia, Sheikh Ahmad, Khairy Zoheir, Abdelkader Ashour, Ashok Kumar. Development of novel selective tumor-associated carbonic anhydrase inhibitors as promising anticancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-100. doi:10.1158/1538-7445.AM2015-LB-100
Abstract LB-107: Targeting ATR using a novel ATR inhibitor AZD6738 in human gastric cancer cells
Authors: Min Ahrum , Im Seock-Ah , Jang Hyemin , Kim Seongyeong , Lee Miso , Kim Jungeun , Lee Kyung-Hun , Han Sae-Won , Kim Tae-Young , Oh Do-Youn , Kim Tae-You , Kim Woo-Ho , Bang Yung-Jue 
Published: August 2015

Abstract
Introduction: The DNA repair system is critical for maintaining genomic integrity. In particular, the homologous recombination (HR) repair pathway, on that repairs DNA double-strand breaks (DSBs), is directly associated with cancer development. Many cancer cells could contain mutations in genes involved in the HR pathway including BRCA1/2, ATM, ATR, and RAD51. ATR can be activated by various types of DNA damage and it initiates DNA damage-induces signaling cascade. As a result, ATR pathway components are considered promising therapeutic targets because ATR inhibition is likely to have greater deleterious effect on cancer cells.
Materials and Methods: The antiproliferative activity of AZD6738 was examined in vitro using a cytotoxic assay, cell cycle analysis, and western blotting. To figure out the action mechanism of AZD6738 in gastric cancer cells, the expression of proteins which participate in DNA repair were investigated. The accumulation of DNA damage was also assessed with a DNA comet assay. These in vitro data were validated in vivo using a human gastric cancer xenograft model.
Results: Human gastric cancer cell lines showed heterogeneous response to AZD6738. In AZD6738 sensitive cells, ATR inhibition leads to the accumulation of unrepaired DSBs due to dysfunctional RAD51 foci formation along with increased caspase 3-dependent cell death and S phase cell cycle arrest. Compared with sensitive cells, the activation of ATM-chk2 signaling pathway under the ATR inhibition was observed in the AZD6738 insensitive cells. It suggests that the activation of ATM-chk2 signal leads to attenuation of AZD6738 sensitivity. Furthermore, AZD6738 significantly suppressed tumor growth with increased apoptosis in vivo.
Conclusion: We evaluated the anti-tumor activity of AZD6738 in gastric cancer in vitro and in vivo model. This is the first study to show that AZD6738 interferes with RAD51-mediated homologous recombination, as well as promotes cell death by inducing S cell cycle arrest and apoptosis in gastric cancer cells. Our findings can help to promote novel treatment strategies using AZD6738 in gastric cancer.
Citation Format: Ahrum Min, Seock-Ah Im, Hyemin Jang, Seongyeong Kim, Miso Lee, Jungeun Kim, Kyung-Hun Lee, Sae-Won Han, Tae-Young Kim, Do-Youn Oh, Tae-You Kim, Woo-Ho Kim, Yung-Jue Bang. Targeting ATR using a novel ATR inhibitor AZD6738 in human gastric cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-107. doi:10.1158/1538-7445.AM2015-LB-107
Abstract LB-132: Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes
Authors: Alcantara Llaguno Sheila R. , Wang Zilai , Sun Daochun , Chen Jian , Xu Jing , Kim Euiseok , Hatanpaa Kimmo , Raisanen Jack , Burns Dennis , Johnson Jane , Parada Luis F. 
Published: August 2015

Abstract
A central question in glioblastoma multiforme (GBM) research is the hierarchy of tumor-initiating cells, and its contribution to the malignant phenotype and genomic make-up of GBM. We examine the potential of adult lineage restricted central nervous system (CNS) progenitors to form malignant gliomas. We show that targeting of Nf1,p53 and Pten mutations in adult CNS progenitors but not stem cells gives rise to fully penetrant GBM. We identify two phenotypically and molecularly distinct GBM subtypes that arise from different adult progenitor lineages. Using multiple inducible cre transgenic lines, we demonstrate that murine GBMs are molecularly separable based on the cell of origin. The oligodendrocyte progenitor cell-derived murine tumors have parallels with a subset of human high-grade gliomas with oligodendrocytic component, tumors that have been ascribed better prognosis compared to classic malignant astrocytomas. These studies indicate that two independent sources of GBM-initiating adult progenitors are susceptible to identical mutations and point to the cell of origin as a major determinant of GBM subtype.
Citation Format: Sheila R. Alcantara Llaguno, Zilai Wang, Daochun Sun, Jian Chen, Jing Xu, Euiseok Kim, Kimmo Hatanpaa, Jack Raisanen, Dennis Burns, Jane Johnson, Luis F. Parada. Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-132. doi:10.1158/1538-7445.AM2015-LB-132
Abstract LB-161: Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells
Authors: Ju Young Seok , Tubio Jose , Mifsud William , Fu Beiyuan ,   ICGC Prostate Cancer, Bone Cancer, Breast Cancer Working Groups, Yang Fengtang , Campbell Peter , Stratton Michael 
Published: August 2015

Abstract
Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm and the mitochondrial double membrane. Despite these physical barriers we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements and the features of the fusion fragments indicate that non-homologous end joining and/or replication-dependent DNA double strand break repair are the dominant mechanism involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.
Citation Format: Young Seok Ju, Jose Tubio, William Mifsud, Beiyuan Fu, ICGC Prostate Cancer, Bone Cancer, Breast Cancer Working Groups, Fengtang Yang, Peter Campbell, Michael Stratton. Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-161. doi:10.1158/1538-7445.AM2015-LB-161