bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3462: EGFRvIII-Stat5 signaling enhances glioblastoma cell invasion
Authors: Roos Alison , Dhruv Harshil D. , Peng Sen , Inge Landon J. , Tuncali Serdar , Pineda Michael , Millard Nghia , Winkles Jeffrey A. , Loftus Joseph C. , Tran Nhan L. 
Published: August 2018

Abstract
Glioblastoma Multiforme (GBM) is the most common malignant brain tumor in adults. Most GBM patients succumb to the disease less than one-year post diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio and chemoresistant properties to the tumor cells; therefore, there is a need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the Stat-signaling pathway. Here we report that EGFRvIII activates Stat5 and GBM invasion, in part, by inducing the expression of a previously established mediator of glioma cell invasion and survival, fibroblast growth factor-inducible 14 (Fn14). EGFRvIII-mediated induction of Fn14 expression is dependent upon Stat5 and requires activation of Src, whereas EGFR regulation of Fn14 is dependent upon MEK/ERK-Stat3 activation. Notably, treatment of EGFRvIII expressing GBM cells with the FDA approved Stat5 inhibitor pimozide blocked Stat5 phosphorylation, Fn14 expression, and cell migration. Since EGFR inhibitors display limited therapeutic efficacy in GBM patients, we hypothesize that the EGFRvIII-Stat5-Fn14 signaling pathway represents a node of vulnerability in the invasive GB cell population and that targeting critical effectors in this pathway will limit GBM tumor dispersion, mitigate therapeutic resistance, and increase survival.
Citation Format: Alison Roos, Harshil D. Dhruv, Sen Peng, Landon J. Inge, Serdar Tuncali, Michael Pineda, Nghia Millard, Jeffrey A. Winkles, Joseph C. Loftus, Nhan L. Tran. EGFRvIII-Stat5 signaling enhances glioblastoma cell invasion [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 3462.
Abstract 3467: Growth factor receptor trafficking in neuroblastoma differentiation
Authors: Lesperance Jacqueline , Subramonian Divya , Woodfield Sarah , Guo Rongjun , Bean Andrew , Lopez-Terrada Dolores , Ittmann Michael , Hakim Sara , Zage Peter E. 
Published: August 2018

Abstract
Background/Objectives: UBE4B is an E3/E4 ubiquitin ligase involved in growth factor receptor (GFR) trafficking. The UBE4B gene is located in the chromosome 1p36 region commonly deleted in high-risk neuroblastoma tumors. We have previously identified associations of UBE4B expression with neuroblastoma patient outcomes. However, the functional roles of UBE4B in neuroblastoma tumor differentiation are not known.
Design/Methods: We analyzed the association of UBE4B gene expression with expression of known markers of neuroblastoma tumor differentiation using publicly available databases and screened cell lines and neuroblastoma tumor samples for UBE4B protein expression using Western blot and quantitative immunohistochemistry. We measured UBE4B expression by Western blot in cell lines before and after induction of differentiation with 13-cis-retinoic acid treatment and determined the effects of UBE4B overexpression and depletion on retinoic acid-induced differentiation using continuous live-cell imaging of neurite morphology, immunohistochemistry, and Western blot for markers of differentiation. Effects on signaling through the Ras/MAPK pathway were measured using Western blots.
Results: UBE4B expression was associated with neuroblastoma differentiation in patient tumors, and UBE4B gene and protein expression were associated with expression levels of known markers of neuroblastoma differentiation. Retinoic acid treatment resulted in increased UBE4B expression in retinoic acid-sensitive, but not -resistant, neuroblastoma cells, and UBE4B depletion was associated with increased ERK phosphorylation, increased proliferation, and inhibition of retinoic acid-induced neuroblastoma differentiation.
Conclusion: We have demonstrated associations between UBE4B expression and tumor differentiation in gene expression databases and in neuroblastoma tumor samples, and our data suggests that UBE4B expression is required for retinoic acid-induced differentiation, potentially through effects on activation of the Ras/MAPK pathway. These associations between UBE4B and neuroblastoma differentiation combined with the established role of UBE4B in GFR trafficking suggest that UBE4B-mediated receptor trafficking may contribute to the responses of neuroblastoma tumors to therapy and to the outcomes of patients with neuroblastoma.
Citation Format: Jacqueline Lesperance, Divya Subramonian, Sarah Woodfield, Rongjun Guo, Andrew Bean, Dolores Lopez-Terrada, Michael Ittmann, Sara Hakim, Peter E. Zage. Growth factor receptor trafficking in neuroblastoma differentiation [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 3467.
Abstract 3475: Novel correlation-based network analysis of breast tumor metabolism identifies the glycerol channel protein Aquaporin-7 as a regulator of breast cancer metastasis
Authors: Dai Chen , Arceo Jennifer , Arnold James , Wu Junmin , Dovichi Norman J. , Sreekumar Arun , Li Jun , Littlepage Laurie E. 
Published: August 2018

Abstract
The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. Using GC-MS, LC-MS/MS, and capillary zone electrophoresis (CZE)-MS platforms, we quantified and compared the levels of 374 metabolites in breast tumor tissue from normal tissue and transgenic mouse breast cancer models overexpressing a panel of oncogenes (PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg). Comparison of the metabolite profiles from the tumors identified oncogene-induced metabolic reprogramming of the tumor tissues. To develop a higher order understanding of the driver genes and metabolites in breast cancer, we next developed a discovery-based correlation network analysis that captured interactions between both metabolite and gene expression data. This analysis uniquely identified a metabolic network of metabolites and genes with prognostic value in breast cancer patients, identifying 35 metabolite and 33 gene hubs that are likely integral to breast tumor metabolism. Further MALDI-MS based imaging revealed heterogeneous distribution of hub metabolites between stromal and epithelial tissue in breast tumors from transgenic mouse models, as well as heterogeneity within the tumor epithelium, suggesting complex metabolic landscape even within the tumor epithelium. We initially focused on the gene hub aquaporin-7 (Aqp7), a water and glycerol channel protein, as a novel regulator of breast cancer. AQP7 deficiency in animal models is associated with adipocyte hypertrophy, increased glycerol and triglyceride accumulation, insulin resistance, and obesity. We discovered that AQP7 is a prognostic marker of overall survival and metastasis in breast cancer patients. Aqp7 is expressed in the epithelium and adipocytes in normal and tumor breast tissue. Reduced Aqp7 expression in mouse breast cancer cells decreased both proliferation and lung metastatic burden. These data suggest AQP7 promotes invasive phenotypes of breast cancer progression. Using an unbiased, discovery-based approach, this study shed light on important players in breast cancer metabolism from a new perspective that complements current guided network analyses.
Citation Format: Chen Dai, Jennifer Arceo, James Arnold, Junmin Wu, Norman J. Dovichi, Arun Sreekumar, Jun Li, Laurie E. Littlepage. Novel correlation-based network analysis of breast tumor metabolism identifies the glycerol channel protein Aquaporin-7 as a regulator of breast cancer metastasis [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 3475.
Abstract 3494: Downregulation of SREBPs inhibited colon cancer cell growth and tumor initiation by alteration of metabolism
Authors: Wen Yang-an , Xiong Xiaopeng , Zaytseva1 Yekaterina , Gao Tianyan 
Published: August 2018

Abstract
Sterol regulatory element binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. There are three SREBP isoforms, SREBP1a, SREBP1c and SREBP2, have been identified in mammalian cells. SREBP1a and SREBP1c are derived from a single gene through the use of alternative transcription start sites. Increasing evidence suggests that increased lipogenesis is needed for cancer cells to accommodate high rates of proliferation. Activation of SREBP1 and enhanced expression of its target genes have been observed in different types of human cancers. However, the functional importance of SREBPs in colon cancer remains to be fully elucidated. In this study, we investigated the role of SREBP-mediated lipid biosynthesis in promoting tumor growth and initiation by regulating cellular metabolism in colon cancer. Knockdown of SREBP-1 or SREBP-2 decreased the expression of target genes required for lipid biosynthesis and levels of fatty acids and triacylglycerides in colon cancer cells. Bioenergetic analysis using Seahorse XF96 Extracelluar Flux Analyzer revealed that silencing SREBP-1 or SREBP-2 expression reduced the mitochondrial respiration, glycolysis, as well as fatty acid oxidation suggesting an inhibition of cellular metabolism. As a result, the rate of cell proliferation and the ability of cancer cells to form tumor spheroids in suspension were decreased. Similar results were obtained in colon cancer cells in which SCAP, an upstream protease responsible for activating SREBP-1 and SREBP-2, was silenced. Mechanistically, downregulation of SREBPs inhibited the activation of AMPK and Akt signaling. Furthermore, knockdown of SREBP-1 or SREBP-2 inhibited xenograft tumor growth in vivo and significantly decreased the expression of genes associated cancer stem cells. Taken together, our findings establish the molecular basis of SREBPs-dependent metabolic regulation and provide a rationale for targeting fatty acid synthesis as a promising approach in colon cancer treatment.
Citation Format: Yang-an Wen, Xiaopeng Xiong, Yekaterina Zaytseva1, Tianyan Gao. Downregulation of SREBPs inhibited colon cancer cell growth and tumor initiation by alteration of metabolism [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 3494.
Abstract 3495: Trip13, a target of miR192, facilitates colorectal cancer progression through WNT/β-catenin signaling
Authors: Agarwal Sumit , Chakravarthi Balabhadrapatruni V. , Chandrashekar Darshan S. , Guo Rong Jun , Datta Pran , Varambally Sooryanarayana , Manne Upender 
Published: August 2018

Abstract
Most colorectal cancers (CRCs) exhibit genomic instability or chromosomal instability (CIN) in the form of aneuploidy. These aberrations are associated with chromosomal gains or losses. In human malignances, levels of a member of the AAA-ATPases family, TRIP13, correlate with CIN. In the present study, we investigated the expression and biological function of TRIP13 in CRC. In silico gene expression profiling using the UALCAN (http://ualcan.path.uab.edu/) web portal showed elevated TRIP13 expression in CRCs as compared to normal/benign colonic epithelial tissues. Studies employing immunoblot analyses confirmed elevated expression of the TRIP13 protein in CRC tissues compared to their matched normal/benign colorectal tissues. Concurrent immunohistochemical analysis of tissue microarrays, containing normal and tumor tissues, further validated cytoplasmic TRIP13 expression in CRCs as compared to their contiguous normal/benign epithelial components. To understand the functional significance of TRIP13 in CRCs, particularly in regard to progression of cancer cells, experiments were performed by utilizing lentivirus-mediated TRIP13 silencing in CRC cell lines that express high levels of TRIP13. Depletion of TRIP13 impeded cell proliferation, colony formation, invasion, cell motility, and spheroid-forming capacity. TRIP13 depletion also showed suppression of EGFR activation and WNT/β-catenin signaling. Furthermore, bioinformatic analysis revealed that TRIP13 is a predicted target of miR192. Dual-luciferase reporter assays showed that miR192 binds to the 3' UTR of TRIP13. Also, overexpression of miR192 in HCT116 cells lowered TRIP13 expression and reduced cell proliferation, colony formation, and invasion, suggesting that it is a tumor suppressor. Thus, these findings demonstrate a function of TRIP13 in the progression of CRCs and indicate that TRIP13 inhibition by small molecules is a possible strategy for treatment of CRC.
Citation Format: Sumit Agarwal, Balabhadrapatruni V. Chakravarthi, Darshan S. Chandrashekar, Rong Jun Guo, Pran Datta, Sooryanarayana Varambally, Upender Manne. Trip13, a target of miR192, facilitates colorectal cancer progression through WNT/β-catenin signaling [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 3495.
Abstract 3496: GC1118, a novel anti-EGFR andtibody, shows more potent antitumor activity regardless of KRAS mutation or high-affinity lignad stimulation compared with cetuximab in gastric cancer
Authors: Park Ji Eun , Jin Mei Hua , Nam Ah-Rong , Bang Ju-Hee , Oh Do-Youn , Bang Yung-Jue 
Published: August 2018

Abstract
Background: EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, cetuximab and panitumulab, anti-EGFR antibodies, have failed to improve overall survival of GC patients compared with standard chemotherapy alone. GC1118 is a novel anti-EGFR antibody with distinct binding epitope compared to cetuximab or panitumumab, and has superior inhibitory activity against high-affinity EGFR ligands (Mol Cancer Ther 2016). In this study, GC1118 was tested to evaluate the antitumor effects in gastric cancer cells.
Methods: Using a total of 15 kinds of GC cell lines (SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-28, MKN-45, NCI-N87, and KATO-), GC1118, cetuximab, cisplatin, and 5-FU were tested. Cells were treated with or without high-affinity EGFR ligands, EGF 20ng/mL or HB-EGF 100ng/mL.
Result: GC1118 exhibited more potent antigrowth effects in the majority of GC cells than cetuximab in colony forming assay and MTT assay, regardless of KRAS mutation status of cells. The synergistic efficacy was observed when cells were treated with GC1118 in combination with cytotoxic chemotherapeutic agents (cisplatin or 5FU) in colony formation assay and migration assay compared to each treatment alone, even under the EGFR-ligand stimulation condition. GC1118 significantly blocked the p-AKT or p-ERK signaling under the presence of ligand induced-EGFR activation. However, cetuximab failed to block p-AKT or p-ERK that was upregulated by EGF or HB-EGF. Moreover, this signal-blocking activity was more potent in case of GC1118 compared with cetuximab in the chemotherapy combination experiment.
Conclusion: GC1118 showed more potent antitumor effects in GC compared with cetuximab. In combination with cytotoxic chemotherapy, GC1118 also has more potent activity compared with cetuximab regardless of KRAS mutation status or high-affinity ligand stimulation condition. This study supports further clinical development of GC1118 in gastric cancer.
Citation Format: Ji Eun Park, Mei Hua Jin, Ah-Rong Nam, Ju-Hee Bang, Do-Youn Oh, Yung-Jue Bang. GC1118, a novel anti-EGFR andtibody, shows more potent antitumor activity regardless of KRAS mutation or high-affinity lignad stimulation compared with cetuximab in gastric 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 3496.
Abstract 3499: The mutational status of residue Y842 in FLT3 predicts the drug response in acute myeloid leukemia
Authors: Kazi Julhash U. , Rönnstrand Lars 
Published: August 2018

Abstract
The type III receptor tyrosine kinase FLT3 plays important roles in the development of early hematopoietic progenitor cells and is found to be mutated in around 35% of all cases of acute myeloid leukemia (AML). AML is a heterogeneous disease that affects the myeloid lineage of blood cells. Wild-type FLT3 needs its ligand, FL, for signal transduction. However, the oncogenic mutants are constitutively active even in the absence of ligand. Similar to the other type III receptor tyrosine kinases, such as KIT, CSF1R, PDGFRA and PDGFRB, ligand binding to the FLT3 induces dimerization, activation of the receptor and auto-phosphorylation. Tyrosine phosphorylation sites in FLT3 create docking sites for interacting proteins which transduce signals linked to survival and proliferation, among other things. Although the most common mutations in FLT3 includes the internal tandem duplication (ITD) mutations in the juxtamembrane domain of FLT3, point mutations in the kinase domain also occur. The so-called activation loop tyrosine residue is well conserved in all receptor tyrosine kinases and has long been known to be essential for the activity of some but not all receptor tyrosine kinases. Recently we have shown that activation loop tyrosine residue in KIT is not essential for its activation but plays an important role in regulating receptor stability and downstream signaling. The activation loop tyrosine residue in FLT3 (Y842) has been found to be mutated in some AML patients and acquired mutations of this residue results in drug resistance when combined with FLT3-ITD. We observed that different Y842 mutants (Y-to-F, Y-to-C and Y-to-H) display differential binding affinity for kinase inhibitors. Expression of Y-to-F mutant in myeloid cells resulted in impaired activation of ERK1/2 through reduced recruitment of SHP2 to the receptor. Furthermore, mice xenografted with myeloid cells expressing this Y-to-F mutant of FLT3, in FLT3-ITD background, resulted in delayed tumor formation. Gene set enrichment analysis (GESA) demonstrated that the Y-to-F mutation causes suppression of anti-apoptotic genes. Taken together, our data suggest that the activation loop tyrosine residue in FLT3 plays an important role in FLT3 downstream signaling and drug sensitivity.
Citation Format: Julhash U. Kazi, Lars Rönnstrand. The mutational status of residue Y842 in FLT3 predicts the drug response 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 3499.
Abstract 3520: Targeting lipid metabolism eradicates peritoneal metastases of ovarian cancer
Authors: Chen Run , Chan David 
Published: August 2018

Abstract
Ovarian cancer is one of the deadliest women malignancies in the world. The chemoresistance accompanied with metastasis lead to high mortality of this disease. Different from other solid tumors, the advanced ovarian cancers prefer transcoelomic route in metastasis. Clinical observation indicates ovarian cancer patients with intraperitoneal metastases are closely association with poor prognosis. Emerging evidence has indicated that ascites fluids which acts as a reservoir providing plenty of growth factors, chemokines and importantly, free fatty acids etc. However, the significance of ascites microenvironment in governing ovarian cancer metastatic progression remain unclear. Herein, we report that the ascites microenvironment alters metabolism that in turn, enhances ovarian cancer cell aggressiveness. By mimicking the ascites microenvironment, we established omental conditioned medium (OCM). Ovarian cancer cells co-cultured in OCM showed enhanced ovarian cancer oncogenic capacities as observed in ascites. By RNA-Seq and proteomics analyses, we found the activities of lipid metabolism were elevated in ovarian cancer cells cultured in OCM. Depletion of Glut-1/-3/-4 by shRNAi approach or treatment of STF31, a glycolysis inhibitor, showed no or slight effect on ATP production and cell growth of ovarian cancer cells. In contrast, knockdown of Acetyl-CoA Carboxylase-α or -β (ACC1/2) or treatment of FASN inhibitor, Orlistat, significantly inhibited the ATP production and cell growth, suggesting ovarian cancer cells undergone a metabolic shift from aerobic glycolysis to β-oxidation when co-cultured in fatty acid enriched OCM. On the other hand, AMP-activated protein kinase (AMPK) is a key energy sensor and affects oncogenic capacities of many cancer cells. We found that its activity was induced initially for triggering fatty acid oxidation in ATP production. But the AMPK activity was gradually reduced due to the negative feedback loop of high ATP content. The lowered AMPK activity led to mTOR and TAK1/NF-κB signaling activation that result in the increased oncogenic capacities of ovarian cancer cells. Notably, inhibition of the above signaling pathways by a combined cocktails of AMPK activator, TAK1 and FASN inhibitors could remarkably impair OCM-mediated oncogenic properties of
ovarian cancer cells in vitro and in vivo. Taken together, these findings suggest that the ascites microenvironment induces metabolic reprogramming for ovarian cancer cells in production of energy supporting their aggressiveness, while targeting the lipid metabolism and associated signalings could impede peritoneal metastases of ovarian cancer.
Citation Format: Run Chen, David Chan. Targeting lipid metabolism eradicates peritoneal metastases of ovarian 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 3520.