bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1408: p53-directed translational control can shape and expand the universe of p53 target genes
Authors: Zaccara Sara , Tebaldi Toma , Ciribilli Yari , Bisio Alessandra , Inga Alberto 
Published: May 2015

Abstract
Several genome-wide transcriptome analyses that focused on p53-induced cellular responses in many cellular contexts have continued to expand the already vast p53-regulated transcriptional networks. To investigate post-transcriptional controls as an additional dimension of p53-directed gene expression responses we performed translatome analysis by polysomal profiling on MCF7 cells treated with Doxorubicin and Nutlin-3a. A comparison between the transcriptome and the translatome revealed a considerable level of uncoupling, meaning genes whose transcription did not correlate with translation. Interestingly, this genes category was significantly associated to apoptosis, DNA and RNA metabolism as well as cell cycle functions, suggesting that post-transcriptional control can modulate classical p53-regulated responses. Furthermore, even for well-established p53 targets that were differentially expressed both at transcriptional and translational levels, quantitative differences between transcriptome, subpolysomal and polysomal RNAs were evident. Seeking mechanisms underlying gene expression uncoupling, we identified p53-dependent modulation of five RNA binding proteins where hnRNPD (AUF1) and CPEB4 are direct p53 transcriptional targets and SRSF1, DDX17, YBX1 are indirect targets modulated at translational level in a p53-directed manner. In particular, YBX1 translation appeared to be reduced by p53 via two different mechanisms, one related to mTOR inhibition and the second to miR-34a expression. Overall, we establish p53 as a master regulator of translational control and identify new p53 target genes affecting translation that can contribute to p53-dependent cellular responses.
Citation Format: Sara Zaccara, Toma Tebaldi, Yari Ciribilli, Alessandra Bisio, Alberto Inga. p53-directed translational control can shape and expand the universe of p53 target genes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1408. doi:10.1158/1538-7445.AM2014-1408
Abstract 1410: Gnaq/11 mutant uveal melanoma is susceptible to Brd4 inhibition by JQ1
Authors: Ambrosini Grazia , Schwartz Gary K. 
Published: May 2015

Abstract
Uveal melanoma (UM) represents the most common intraocular malignancy in the United States, and there are no effective treatments for this aggressive disease. Uveal melanoma is characterized by oncogenic mutations in Gnaq and Gna11, which activate the mitogen-activated protein kinase pathway (MAPK). Furthermore, both primary and metastatic UM are characterized by genetic abnormalities, including the amplification of the chromosomal arm 8q and monosomy of chromosome 3, which are significantly associated with poor prognosis. The oncogene MYC, which is located on 8q24.1, is amplified in nearly 70% of uveal melanoma, and is also regulated by the MAPK pathway. Chromatin regulators have become attractive targets for cancer therapy. In particular, the BET-bromodomain inhibitor JQ1 has shown selective inhibition of c-Myc expression, followed by the suppression of c-Myc-dependent target genes. We examined the effects of JQ1 in a panel of 8 UM cell lines, including cell lines with Gnaq/Gna11 mutations (92.1, Omm1.3, Mel270, Mel202, Omm1), a cell line with MYC amplification (Mel290), and cells without either mutation or amplification (C918, Mel285). The Gnaq/Gna11 mutant cells were the most sensitive to growth inhibition at nanomolar concentrations of JQ1 (IC50=200nM), followed by the cell line with amplified MYC (IC50=1μM), while the cells without mutation or amplification exhibited little inhibition. We also examined the biochemical effects of JQ1 treatment, which caused a dose- and time-dependent suppression of c-Myc as well as survivin, XIAP, ERK1 and E2F1, while p21and the pro-apoptotic protein Bim were induced in all the cell lines. Interestingly, JQ1 also suppressed the anti-apoptotic protein Bcl-xL and induced PARP cleavage only in the Gnaq/Gna11 mutant cells. Flow cytometric analysis indicated a cell cycle arrest in G1 in all the cell lines and an apoptotic population in sub-G1in the mutant cells. Furthermore, treatment with JQ1 resulted in significant antitumor activity in mouse xenograft models of uveal melanoma with Gnaq mutation. All together, these observations support the evidence that JQ1 represent a promising therapeutic approach for uveal melanoma with Gnaq/Gna11 mutations.
Citation Format: Grazia Ambrosini, Gary K. Schwartz. Gnaq/11 mutant uveal melanoma is susceptible to Brd4 inhibition by JQ1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1410. doi:10.1158/1538-7445.AM2014-1410
Abstract 1411: Regulation of osteoprotegerin expression in breast cancer cells by nuclear factor-kappaB
Authors: Weichhaus Michael , Connelly Linda 
Published: May 2015

Abstract
Acquisition of osteoprotegerin (OPG) expression by breast epithelial cells appears to be linked to the formation of malignant breast neoplasia. Previous in vitro studies demonstrate that OPG expression by breast cancer cells increases resistance to tumor necrosis factor related apoptosis inducing ligand (TRAIL) mediated apoptosis, suggesting a tumor promoting role for OPG. Recently we have observed reduced ability to metastasize in the chick embryo model by MDA-MB-231 breast cancer cells after reducing OPG expression using RNAi methods, further substantiating a tumor promoting role of OPG.
In order to direct inhibitory strategies, we investigated the regulation of OPG expression in human breast cancer cell lines. Based on regulation of OPG in other cell types, we hypothesized that OPG expression is regulated by the transcription factor Nuclear Factor-kappaB (NF-kappaB).
OPG expression was examined in MDA-MB-231 (basal, triple negative), MCF-7 (luminal, ER-positive) and SK-BR-3 (HER-2 positive) breast cancer cells. We used real time RT-PCR and ELISA to confirm that all cell lines expressed OPG mRNA and protein, respectively. NF-kappaB activity was modulated using thymoquinone (TQ; 10 µM) and BMS345541 (1 µM; both inhibitors) and Tumor Necrosis Factor-alpha (TNF-alpha) and Interleukin-1-beta (IL-1-beta; 10 ng/ml, both activators). Specificity for these modulators was determined by NF-kappaB promoter driven luciferase reporter assay.
In MDA-MB-231 cells, inhibition of NF-kappaB lowered basal levels of OPG mRNA and protein expression, suggesting constitutive NF-kappaB activity plays a role in OPG expression. TNF-alpha and IL-1-beta treatment increased OPG mRNA and protein expression significantly above basal levels. Inhibition of NF-kappaB ameliorated TNF-alpha and IL-1-beta induced OPG expression to baseline. In MCF-7 and SK-BR-3 cells, basal levels of OPG mRNA and protein expression were not reduced by the NF-kappaB inhibitors. TNF-alpha and IL-1-beta treatment increased OPG mRNA and protein expression significantly above baseline, however inhibition of NF-kappaB did not ameliorate the induction of OPG mRNA and protein expression.
Our data suggests that the mechanisms regulating OPG expression in breast cancer cells may depend on breast cancer subtype. It appears in the basal cell line, MDA-MB-231, NF-kappaB's tumor promoting effects may be modulated in part by increasing OPG expression. The regulation of OPG expression in cells from other breast cancer subtypes requires further investigation.
Citation Format: Michael Weichhaus, Linda Connelly. Regulation of osteoprotegerin expression in breast cancer cells by nuclear factor-kappaB. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1411. doi:10.1158/1538-7445.AM2014-1411
Abstract 1412: Capturing c-Myb target genes in adenoid cystic carcinoma
Authors: BRAYER KATHRYN , Ness Scott 
Published: May 2015

Abstract
Mutated versions of c-Myb are potent oncoproteins, and Myb proteins are over- or highly-expressed in a wide variety of human tumors. Adenoid Cystic Carcinoma (ACC), the second most frequent malignancy of minor and major salivary glands, frequently contains a recurrent t(6;9) translocation which fuses the c-Myb proto-oncogene on chromosome 6q to the NFIB gene on chromosome 9p resulting in the expression of novel Myb-NFIB fusion oncoproteins. These variants of c-Myb play a definitive role in development of ACC tumors, and are the first evidence that Myb proteins function as “driver” mutations in human cancer. Identifying target genes directly regulated by Myb-NFIB oncoproteins in ACC tumors can help determine how Myb proteins transform cells and contribute to tumor development in ACC.
Genomics analyses of solid tumors is challenging because tumors are often heterogeneous tissue types and are often not stored in a manner that preserves labile nucleic acids. FFPE samples offer the most promise since formaldehyde fixation effectively “locks” the Myb-NFIB fusion proteins and epigenetic marks, such as modified histones, to the genes of interest. We have developed improved methods were for extracting chromatin from FFPE samples for use in chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) and are applying these technical innovations to ACC tumors preserved in FFPE. When combined with gene expression information provided by RNA-seq analysis, ChIP-seq analysis of c-Myb gene targets will identify regulators that can be targets in novel therapeutic strategies in the future, as well as provide a greater understand of c-Myb functions in ACC and other epithelial tumors in which Myb plays a role.
Citation Format: KATHRYN BRAYER, Scott Ness. Capturing c-Myb target genes in adenoid cystic carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1412. doi:10.1158/1538-7445.AM2014-1412
Abstract 1422: Validation of primary non-small cell lung cancer model: Stable isotope-resolved metabolomics (SIRM) reveals functional biochemistry
Authors: Kinslow Connor J. , Fan Teresa W-M , Tan Jin L. , Lorkiewicz Pawel K. , Balasubramaniam Ramya , Cai Yihua , Yan Jun , Lane Andrew N. 
Published: May 2015

Abstract
Stable isotope-resolved metabolomics (SIRM) provides a comprehensive and functional readout of cellular activity and is therefore a useful tool both for biomarker discovery and fundamental cancer biology. We have established a primary lung squamous cell carcinoma line (PSLC1), isolated from the lung tumor tissue of a non-small cell lung cancer patient, for which the metabolic profile has been established. We used SIRM to characterize the metabolic activity of the cells in mouse xenografts and in cell culture. Here we report the metabolic activities of the cell line in culture using two different tracers to evaluate central metabolism. PSLC1 cells were grown in either [U-13C]-glucose or [U-13C,15N]-glutamine labeled medium. Cell extracts and medium were prepared and analyzed by 1H-NMR, HSQC, TOCSY, GC-MS, and FTICR-MS. Cells exhibited linear glucose consumption that persisted even as proliferation plateaued. The conversion of glucose to lactate occurred at a strikingly high 89%. Anaplerotic pathways involving pyruvate carboxylation and glutaminolysis were active and appeared to be dependent on cellular proliferation. Glutamine represented an important contributor for biosynthetic and bioenergetic cellular needs, including de novo pyrimidine biosynthesis and glucose-independent TCA cycling. In addition, glutamine served as the major precursor in proline and glutathione biosynthesis. Distinct glutamine utilization and labeling patterns indicated that this cancer might be driven by C-MYC overexpression. C-MYC overexpression was observed by targeted protein analysis guided by metabolomics-edited transcriptomics analysis (Pro-META). The ability of SIRM to generate hypotheses about protein expression demonstrates its potential use as a first line biomarker detection method. Comparison with upstream in situ and xenograft data will allow us to assess model validity and the effects of tumor microenvironment. In turn, the in vitro data will help us interpret human in situ data more robustly. Supported by grant R25-CA-134283 and 1P01CA163223-01A1 from the National Cancer Institute
Citation Format: Connor J. Kinslow, Teresa W-M Fan, Jin L. Tan, Pawel K. Lorkiewicz, Ramya Balasubramaniam, Yihua Cai, Jun Yan, Andrew N. Lane. Validation of primary non-small cell lung cancer model: Stable isotope-resolved metabolomics (SIRM) reveals functional biochemistry. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1422. doi:10.1158/1538-7445.AM2014-1422
Abstract 1423: Resistance to LDHA inhibitors requires signaling through the AMPK/mTOR/S6K pathway leading to increased oxidative phosphorylation
Authors: Boudreau Aaron , Peterson David , Moffat John , Liu Bonnie , Kwong Mandy , Gao Min , Purkey Hans , O'Brien Thomas , Hatzivassiliou Georgia , Daemen Anneleen , Evangelista Marie 
Published: May 2015

Abstract
Lactate Dehydrogenase A (LDHA) is an attractive candidate for targeting glycolysis-addicted tumors. However, due to the inherent plasticity of metabolic networks in cells, there is concern that the benefit of targeting LDHA may be transient and that resistance will quickly emerge. To identify predictive features of LHDA inhibitor sensitivity and to understand how cells adapt to long-term LHDA inhibition, we screened a large panel (∼500) of tumor cell lines with GNE-140, a newly developed LHDA inhibitor. We found that approximately 15% of lines were inherently sensitive to the LDHA inhibitor, with sensitivity correlating with increased expression of glycolysis genes and inversely correlating with expression of oxidative phosphorylation genes. Despite the metabolic plasticity of cells, the timing of acquired resistance to LDHA inhibitors was comparable with other targeted agents. Under long-term LDHAi treatment, glycolytic cells acquired resistance by increased oxidative phosporylation (OX-PHOS) in a mechanism dependent on the AMPK stress response pathway; targeting either AMPK, downstream kinases, or OX-PHOS using tool compounds synergized with and prevented acquired resistance to GNE-140. Taken together, our data suggests that targeting anaerobic glycolysis may benefit a subset of patients across indications and that combinations with agents that block AMPK signaling or the mitochondria will be effective at delaying tumor relapse.
Citation Format: Aaron Boudreau, David Peterson, John Moffat, Bonnie Liu, Mandy Kwong, Min Gao, Hans Purkey, Thomas O'Brien, Georgia Hatzivassiliou, Anneleen Daemen, Marie Evangelista. Resistance to LDHA inhibitors requires signaling through the AMPK/mTOR/S6K pathway leading to increased oxidative phosphorylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1423. doi:10.1158/1538-7445.AM2014-1423
Abstract 143: Non-canonical role of TAM receptors in breast cancer
Authors: Hsieh Shelly , Nguyen Khanh Q. , Kimani Stanley , Birge Raymond B. 
Published: May 2015

Abstract
TAM receptors (Tyro-3, Axl, Mer) are a family of three homologous receptor tyrosine kinases that play a role in the phagocytosis of apoptotic cells (a process termed efferocytosis in recent years). TAM receptors on the surface of epithelial cells bind to soluble ligands Gas6 and Protein S, which in turn, bind to phosphatidylserine-expressing apoptotic cells. After epithelial cells phagocytose apoptotic cells, they release anti-inflammatory cytokines (e.g. IL-10, TGFβ) to attenuate the immune response. This non-canonical role of TAM receptors as efferocytosis receptors is in addition to their well-studied canonical role as tyrosine kinase receptors that activate cell proliferation signaling pathways (e.g. PI3K, Ras, ERK). Therefore, overexpression of TAM receptors on cancer cells has a dual effect on tumor progression. To date, TAM receptors have been implicated in numerous cancers, including breast cancer; and various family members have been shown to be overexpressed in mouse and human mammary tumor cells. We propose that efferocytosis is a unique and novel oncogenic event by virtue of its role in the production of immunosuppressing factors into the tumor microenvironment. To study this, we set up a unique 3D acini model, where luminal apoptotic cells are engulfed by the basal cells of the acini. Using this system along with 2D cultures, we demonstrated that overexpression of Mer increased the rate of efferocytosis, but does not act as a classical oncogene by filling in the luminal space. Additional studies such as time-lapse studies of acini stained with caspases showed that Mer increased the rate of clearance. This adapted method offers a unique system to study cancer cell efferocytosis, and the role of TAM receptors in cancer progression and immune evasion.
Citation Format: Shelly Hsieh, Khanh Q. Nguyen, Stanley Kimani, Raymond B. Birge. Non-canonical role of TAM receptors in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 143. doi:10.1158/1538-7445.AM2014-143
Abstract 1430: Identification of distinct metabolic subtypes within pancreatic ductal adenocarcinoma through broad metabolite profiling
Authors: Daemen Anneleen , Peterson David , Sahu Nisebita , McCord Ron , Kowanetz Kaska , Hitz Anna , Du Xiangnan , Liu Bonnie , Gao Min , Moffat John , Hong Rebecca , Sampath Deepak , Merchant Mark , O'Brien Thomas , Yauch Bob , Settleman Jeff , Qing Jing , Hatzivassiliou Georgia , Evangelista Marie A. 
Published: May 2015

Abstract
Targeting cancer metabolism is currently being evaluated as a potential therapeutic target. Identification of tumor subtypes with specific metabolic requirements will enable the success of such therapies. Using cell line models of pancreatic ductal adenocarcinoma (PDAC), we conducted broad metabolite profiling and identified 3 metabolic subtypes through non-negative matrix factorization (NMF) consensus clustering. Among the most distinguishing features between the subtypes were levels of metabolites important for lipid synthesis, amino acid, and energy-related pathways, suggestive of distinct metabolic dependencies. Using RNAseq we show that these subtypes are defined at the transcriptional level and are associated with known subtypes of PDAC. In metabolic flux experiments, we also show that glucose and glutamine are differentially utilized by each subtype, and as a consequence, exhibit distinct sensitivity to inhibition of various metabolic pathways. Finally, through screening of a large panel of tumor cell lines with various metabolic inhibitors, we cross-validate our finding in PDAC and provide strong evidence that these same subtypes exist and can be identified in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity to metabolic inhibitors in cancer cells.
Citation Format: Anneleen Daemen, David Peterson, Nisebita Sahu, Ron McCord, Kaska Kowanetz, Anna Hitz, Xiangnan Du, Bonnie Liu, Min Gao, John Moffat, Rebecca Hong, Deepak Sampath, Mark Merchant, Thomas O'Brien, Bob Yauch, Jeff Settleman, Jing Qing, Georgia Hatzivassiliou, Marie A. Evangelista. Identification of distinct metabolic subtypes within pancreatic ductal adenocarcinoma through broad metabolite profiling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1430. doi:10.1158/1538-7445.AM2014-1430
Abstract 1433: Omental derived adipose stromal cells regulate nitric oxide homeostasis to maintain tumorigenicity in ovarian cancer cells
Authors: Rizi Bahar Salimian , Klopp Ann H. , Nagrath Deepak 
Published: May 2015

Abstract
The rate of obesity is increasing dramatically in the United States, resulting in a rising incidence of obesity associated diseases including colorectal, gallbladder, esophageal, renal, breast, endometrial and ovarian cancer. The location of excess adipose tissue is reportedly an important factor which influences the effect of obesity on cancer incidence. The tumor promoting effects of regional adipose may be attributed, at least in part, to the presence of mesenchymal stem cell (MSC) population in adipose tissue. Adipose derived stromal cells (ASCs) are a multi-potent population of MSCs, which support cancer progression in many models. These cells are uniquely tumor tropic, migrating into tumor stroma from regional sources where they support formation of tumor stroma elements and promote tumor progression. Thus, we hypothesize that the omentum provides a particularly hospitable microenvironment for OVCA metastasis due to the presence of omental ASCs (O-ASCs). One critically important, yet often overlooked contributor to ovarian tumor growth, progression and metastasis in obese individuals is nitric oxide (NO). Cancer cells' high affinity for NO and NO's characteristic high solubility in lipids could explain the proximity of many carcinomas to fatty tissue, and thus the high positive correlation between obesity and cancer. Here we report a novel NO mediated reciprocal coupling between O-ASCs and ovarian cancer which promotes cancer cell growth and energy metabolism. Our results show that O-ASCs supports viability of cancer cells by secreting arginine and cancer cells in turn induce adipogenesis in O-ASCs by secreting citrulline. We found that OASCs promote tumor growth and increase resistance to chemotherapy by modulating NO homeostasis. The inhibition of NO synthesis or scavenging of NO enhanced chemo-sensitivity. Using metabolic profiling we found that OASCs rewire metabolic pathways related to nitrogenous amino acids and reprogram energy metabolism. In summary, our data indicate that modulation of intrinsic NO substantially affects tumor growth and drug toxicity in ovarian cancer cells. Our study will lead to significant advances in the understanding of the omentum in altering cancer metabolism and lead to novel therapeutics.
Citation Format: Bahar Salimian Rizi, Ann H. Klopp, Deepak Nagrath. Omental derived adipose stromal cells regulate nitric oxide homeostasis to maintain tumorigenicity in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1433. doi:10.1158/1538-7445.AM2014-1433