bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 803: Identification of compensatory pathway for glutamate production
Authors: Asaka Ryoichi , Nguyen Tu , Krisch Brian J. , Nabi Karim , Quinones Addison , Tan Jessica , Antonio Marjorie J. , Li Ting , Camelo Felipe , Nguyen Kiet , Udupa Sunag , Gabrielson Edward , Le Anne 
Published: August 2019

Abstract
Measurement and Methods: In this study, we sought to expand our knowledge of glutamine metabolism beyond glutaminolysis. Using mass spectroscopy-based stable isotope-resolved metabolomics (SIRM) with 13C515N2-labeled-glutamine, we precisely identified the metabolites produced from glutamine both in vitro and in vivo. Tumors were harvested 2 hours post first glutamine injection. Metabolites were then extracted from tumors, and analyzed using Agilent 6520 Q-TOF mass spectrometer and 1H-NMR. Metabolite intensities were later normalized to protein concentration following analysis.
Results: Our results showed that total glutamate levels were lower in BPTES-NP treated tumors as compared to vehicle control ones. Interestingly, we found an increase in (m+5) labeled glutamate (mass of the parent ions (m) and 5 more mass units due to 13C415N1-glutamate or 13C5-glutamate labelling) in BPTES-NP treated tumors as compared to the vehicle control tumors. Moreover, we found that (m+5) glutamate is a product of (m+7) glutamine being converted to (m+5) alpha-ketoglutaramate (KGM) via glutamine-pyruvate transaminase and further on into alpha-ketoglutarate (aKG) by omega-amidase, which can finally produce the identified (m+5) glutamate through glutamate dehydrogenase. Further analysis using 1H-NMR detailed a significant increase in overall KGM intermediate intensity in treatment groups compared to the control groups, confirming the upregulation of compensatory pathway (glutamine-KGM- aKG-glutamate) to produce glutamate upon treatment of GLS1 inhibitor.
Conclusion: These results explain the reasons behind the limited clinical outcomes for single therapy with a GLS1 inhibitor, and provide potential therapeutic targets: glutamine-pyruvate transaminase, for combination treatments with GLS1 inhibitors to prevent the compensation for glutamate production amid GLS1 inhibition.
Citation Format: Ryoichi Asaka, Tu Nguyen, Brian J. Krisch, Karim Nabi, Addison Quinones, Jessica Tan, Marjorie J. Antonio, Ting Li, Felipe Camelo, Kiet Nguyen, Sunag Udupa, Edward Gabrielson, Anne Le. Identification of compensatory pathway for glutamate production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 803.
Abstract 810: Differential use of lactate for mitochondria respiration by NSCLC cells
Authors: Swain Pamela , Romero Natalia , Kam Yoonseok , Dranka Brian P. 
Published: August 2019

Abstract
Metabolic liabilities in cancer cells provide the opportunity for novel therapeutic approaches. This is especially true as the dogma that all cancer cells are glycolytic is being challenged. Phenotypic screening of cancer cell lines can demonstrate what these liabilities are and suggest approaches for drugs that target these vulnerabilities. As an example, non-small cell lung cancer (NSCLC) is typically driven by oncogenic mutations in either KRAS or EGFR. However, the impact of these mutations on cellular metabolic phenotype is not well-studied. In this study, we observed that the two KRAS-mutated NSCLC cell lines (A549 and H460) primarily relied on glycolysis for ATP production while EGFR-mutated cell lines (H1975 and PC9) were more reliant on mitochondrial respiration to meet energy demands. There is emerging evidence to suggest that lactate is a major fuel for cancer cell energy metabolism especially in the glucose-limited tumor microenvironment. Thus, we next compared the use of lactate with other carbon sources for ATP production in NSCLC cells. We found there was differential usage of lactate for mitochondrial respiration between KRAS and EGFR-mutated NSCLC cells. EGFR-mutated NSCLC cells used lactate and increased mitochondrial respiration when lactate was acutely administrated regardless of glucose availability. In contrast, the use of lactate for the mitochondrial respiration by KRAS-mutated cells was limited. In A549 cells, no significant change in mitochondrial respiration rate was observed at all by acute injection of lactate. Together, these results imply that NSCLC variants have adopted different metabolic phenotypes depending on the oncogenic background and more oxidative phenotype may be correlated to higher lactate use for TCA cycle in production of ATP.
Citation Format: Pamela Swain, Natalia Romero, Yoonseok Kam, Brian P. Dranka. Differential use of lactate for mitochondria respiration by NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 810.
Abstract 812: γ-tocotrienol induces mitophagy in breast cancer cells through activation of LKB1-AMPK pathway
Authors: Dronamraju Venkatesh , Sylvester Paul W. 
Published: August 2019

Abstract
The dysregulation of glucose metabolism in cancer cells manifests as a characteristic phenomenon, referred to as the Warburg effect. Warburg effect is an over-reliance on aerobic glycolysis by cancer cells to meet the energy demand of proliferation. Previous studies have shown that γ-tocotrienol, a natural vitamin E derivative, inhibits aerobic glycolysis in human breast cancer cells through its modulation of key regulatory enzymes protein kinase B (Akt) and 5’-AMP activated kinase (AMPK). In the present study, we investigated the effects of γ-tocotrienol-induced activation of AMPK on mitochondrial dynamics in human breast cancer cells. Western blotting and immunocytochemistry analysis revealed that in human breast cancer cells MDA-MB-231 and T-47D, γ-tocotrienol removed the negative regulation of Akt on liver kinase B1 (LKB1), an upstream promoter of AMPK by increasing active complex formation and cytosolic localization of LKB1. In addition, γ-tocotrienol-induced activation of AMPK improved mitochondrial membrane potential through inhibition of uncoupling protein 1 (UCP1) as revealed by western blot analysis and mitochondrial membrane potential assay. High performance liquid chromatography (HPLC) analysis of NAD+/NADH ratio showed that γ-tocotrienol-induced AMPK activation improved the NAD+ ratio in human breast cancer cells, which indicates improving mitochondrial oxidative phosphorylation. In addition, γ-tocotrienol induced AMPK activation in human breast cancer cells causes increased mitochondrial fission, an indicator of mitophagy, as revealed by Western blot analysis of mitochondrial fission factor (MFF). In summary, these results show that γ-tocotrienol-induced AMPK activation modulates metabolic reprogramming in part by influencing the mitochondrial dynamics in human breast cancer cells. This work was supported in part by funds provided by the Louisiana Cancer Foundation.
Citation Format: Venkatesh Dronamraju, Paul W. Sylvester. γ-tocotrienol induces mitophagy in breast cancer cells through activation of LKB1-AMPK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 812.
Abstract 827: Estimating breast tissue-specific epigenetic age using next-generation methylation sequencing data
Authors: Castle James R. , Lin Nan , Liu Jingpeng , Wang Chi , Liu Yunlong , He Chunyan 
Published: August 2019

Abstract
Epigenetic age captures both genetic and environmental influences across time on cellular functions and is an indicator of biological aging. Epigenetic age may deviate from chronological age substantially in individuals. Epigenetic age is also tissue-specific. Emerging evidence suggests that female breast tissue ages faster than other parts of the body according to epigenetic age estimation using the "Horvath Clock" model. The Horvath method is based on the DNA methylation of 353 CpG loci on the outdated Illumina microarray platforms. The increasing availability of next-generation sequencing data calls for method development that uses DNA methylation sequencing data to estimate tissue-specific epigenetic age. We developed a new method to estimate breast tissue-specific epigenetic aging using next-generation methylation sequencing data and assessed the difference between epigenetic and chronological ages, known as epigenetic age acceleration (EAA), in different breast tissue types. The Illumina TruSeq Methyl Capture EPIC Sequencing technology was used to obtain DNA methylation profiles of approximately 3.3 million CpG sites in 111 tumor, 48 matched adjacent normal, and 462 normal breast tissue samples. A total of approximately 1.4 million CpG sites remained after quality control. Following the Horvath approach, we used an elastic net penalized regression model to regress chronological age on CpG sites in normal breast tissue and defined a new set of 247 clock CpGs specific to breast tissue with randomly divided training (n = 370) and testing (n = 92) data sets. We estimated breast tissue-specific epigenetic age and EAA in tumor, adjacent, and normal breast tissue. We found that breast tissue-specific epigenetic age was positively correlated with chronological age (r=0.87; P&lt;2.2X10-16). Neither normal nor adjacent normal breast tissue showed a significant EAA. However, tumor breast tissue had a significant and increased EAA (median = 8.0 years; P=6.9X10-9). While triple-negative breast tumors showed no significant EAA, hormone receptive-positive and Her2-positive breast tumors had a significant and increased EAA (median=9.5 and 13.1 years; P=1X10-5 and 0.02, respectively). Results of this new model were compared to similar results using the Horvath Clock model and were found to be qualitatively consistent. Further research is needed to determine whether epigenetic age acceleration in normal breast tissue is predictive of breast cancer risk and how breast cancer risk factors influence the rate of acceleration.
Citation Format: James R. Castle, Nan Lin, Jingpeng Liu, Chi Wang, Yunlong Liu, Chunyan He. Estimating breast tissue-specific epigenetic age using next-generation methylation sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 827.
Abstract 833: Integrative analysis of TCGA pancreatic ductal adenocarcinoma data
Authors: Mishra Nitish K. , Southekal Siddesh , Guda Chittibabu 
Published: August 2019

Abstract
Pancreatic cancer is a heterogeneous type of cancer that exhibits different histopathological, molecular and genomic phenomena. Pancreatic ductal adenocarcinoma (PDAC) is the deadliest type of pancreatic cancer with a five-year survival of only 8%. Prognostic biomarkers for early detection of PDAC are not available. In this study, we used clinical, DNA methylation, and gene expression profiles of 146 TCGA PDAC patients. We analyzed the global patterns of DNA methylation and correlated the promoter DNA methylation with corresponding gene expression. CpG sites with a difference of 0.2 in the mean β value of the primary tumor and normal samples were considered as differentially methylated. We observed differential methylation of about 12-thousand CpG sites between tumor and normal samples, the majority of which are hypermethylated. Chromosome 1, 20, 18 and 19 are predominately hypermethylated and chromosome 9 is hypomethylated. CpG islands and regions that are in close proximity to CpG islands (shores) have more hypermethylated sites compared to the far away regions (shelf). Pathway enrichment analysis of differentially methylated genes enabled us to understand how changes in methylation affect biological pathways involved in the progression of PDAC. Our analysis reveals enrichment of MAPK signaling, Rap1 signaling, calcium signaling pathway, etc. Promoter DNA methylation is highly associated with its corresponding gene expression. A significant correlation between methylated CpG sites within 1.5kb from TSS and corresponding gene expression was observed between 4,971 CpGs and 1,744 corresponding genes, out of these about 92% of the genes showed a negative correlation. Survival analysis showed a statistically significant correlation between the expression levels of genes, NEK2, and ASPM with overall survival of the patients. In the future, we will further analyze the long non-coding RNA (lncRNA) promoter methylation, and role of lncRNA and miRNA in PDAC patients’ survival.
Citation Format: Nitish K. Mishra, Siddesh Southekal, Chittibabu Guda. Integrative analysis of TCGA pancreatic ductal adenocarcinoma data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 833.
Abstract 853: Essential role of autocrine FGF19-FGFR4 signaling in head and neck tumorigenesis
Authors: Lang Liwei , Gao Lixia , Shay Chloe , Zhao Xiangdong , Shull Austin , Teng Yong 
Published: August 2019

Abstract
The fibroblast growth factor 19 gene FGF19 has been reported to be amplified in several cancer types and encodes for a key autocrine signaler known to promote tumorigenic growth. Thus, it is imperative to understand which cancers are oncogenically addicted to FGF19 amplification as well as the role it serves in these cancer types. We report for the first time that high FGF19 amplification in head and neck squamous cell carcinomas (HNSCC) is associated with increased autocrine secretion of FGF19 and poor patient outcome in HNSCC. FGF19 amplification corresponded with constitutive activation of FGFR4-dependent ERK/AKT-p70S6K-S6 signaling, and addition of human recombinant FGF19 could promote proliferation and soft agar colony formation in HNSCC cells with low FGF19 expression through activating FGFR4 and downstream signaling cascades. Consistently, FGF19 knockout counteracted the observed effects in HNSCC cells carrying high endogenous FGF19, and significantly suppressed tumor growth in an orthotopic mouse model of HNSCC. This study demonstrates that FGF19 gene amplification corresponds with an increased dependency upon FGF19/FGFR4 autocrine signaling in HNSCC, revealing a therapeutic target for this cancer type.
Note: This abstract was not presented at the meeting.
Citation Format: Liwei Lang, Lixia Gao, Chloe Shay, Xiangdong Zhao, Austin Shull, Yong Teng. Essential role of autocrine FGF19-FGFR4 signaling in head and neck tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 853.
Abstract 864: Mutant IDH1 is essential for chondrosarcoma growth
Authors: Li Luyuan , Hu Xiaoyu , Eid Josiane E. , DeSalvo Joanna , Trent Jonathan C. 
Published: August 2019

Abstract
Chondrosarcomas are malignant bone tumors that produce cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers, including chondrosarcomas. IDH mutations detected in human cancers invariably are heterozygous missense substitutions. These mutations lead to the inability of IDH to convert isocitrate into α-ketoglutarate (α-KG). Instead, α-KG is reduced into 2-hydroxyglutarate (D-2HG), an oncometabolite. Due to the structural similarity between D-2HG and α-KG, it has been reported that high levels of D-2HG competitively inhibit α-KG-dependent dioxygenases such as TET, JHDM and PHD enzymes, thus contributing to tumorigenesis. We sought to determine the role of IDH1 mutations in the tumorigenesis of human chondrosarcomas by inactivating mutant IDH1 using pharmacological and genetic approaches. In our study, we employed two human chondrosarcoma cell lines, JJ012 and HT1080, that carry endogenous IDH1 mutations. IDH mutation analysis was performed by PCR-based DNA sequencing, and D-2HG levels were measured by tandem mass spectrometry. Mutant IDH1 was knocked down via siRNA and knocked out via CRISPR/Cas9. We analyzed the effect of mutant IDH1 on chondrosarcoma growth in murine xenograft models. We found that knockdown of mutant IDH1 via siRNA significantly reduced D-2HG production in chondrosarcoma cells. In addition, mutant IDH1 knockdown dramatically inhibited colony formation in the sarcoma cells. Consistently, genetic knockout of mutant IDH1 almost completely depleted D-2HG production and significantly inhibited colony formation in the chondrosarcoma cells. To assess the significance of these results in vivo, we implanted the mutant IDH1- knockout cells in nude mice and studied their capacity for tumor initiation and growth. In these models, we observed that loss of mutant IDH1 led to a marked attenuation of chondrosarcoma formation. Our findings clearly demonstrate that mutant IDH1 plays a vital role in chondrosarcoma tumor formation. By investigating the role of IDH mutations in the pathogenesis of chondrosarcomas, we aim to uncover the potential therapeutic targets against this aggressive cancer.
Citation Format: Luyuan Li, Xiaoyu Hu, Josiane E. Eid, Joanna DeSalvo, Jonathan C. Trent. Mutant IDH1 is essential for chondrosarcoma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 864.
Abstract 873: Molecular mechanisms of non-small cell lung cancer growth and drug resistance
Authors: Alam SK Kayum , Astone Matteo , Liu Ping , Wang Li , Coyle Abbygail M. , Dankert Erin N. , Hoffman Dane K. , Hall Stephanie R. , Zhang Wei , Kuang Rui , Roden Anja C. , Mansfield Aaron S. , Hoeppner Luke H. 
Published: August 2019

Abstract
Lung cancer is the deadliest and most frequently diagnosed type of tumor worldwide, with 1.6 million deaths reported annually. Non-small cell lung cancer (NSCLC) represents 85% of all lung cancer cases and carries a poor 5-year survival rate below 15%. Prognoses remain dismal due to the large number of patients diagnosed with advanced stage disease and the development of resistance to current therapies. A better understanding of acquired drug resistance will help to circumvent the progression of lung cancer and make significant strides in improving NSCLC patient treatment. Our recent work demonstrates that dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) and its amino-terminally truncated splice variant (t-DARPP) promote lung tumor growth in orthotopic mouse models. IHC staining of 62 human lung adenocarcinoma tissues showed that t-DARPP expression is elevated with increasing tumor (T) staging score, which represents the size of the primary tumor and whether it has grown into nearby areas, as a metric of tumor progression and growth. Correspondingly, a computational biology analysis of 513 lung adenocarcinoma patients revealed upregulation of t-DARPP isoform expression correlates with advanced T stage and is associated with poor overall survival. We identified a novel physical interaction between DARPP-32 and inhibitory kappa B kinase-α (IKKα) that promotes NSCLC cell migration through activation of non-canonical NF-κB2 signaling. It has been shown that DARPP-32 overexpression inhibits gefitinib-induced apoptosis in gastric cancer and t-DARPP contributes to the trastuzumab resistance phenotype in breast cancer. Our recent findings suggest DARPP-32 and t-DARPP overexpression in NSCLC promotes resistance to specific molecular targeted inhibitors by enabling tumor cells to evade apoptosis via Akt- and Erk-dependent cell survival mechanisms. Current ongoing studies are focused on manipulating expression of DARPP-32 isoforms in lung tumor cells to prevent resistance to targeted therapies in NSCLC patients.
Citation Format: SK Kayum Alam, Matteo Astone, Ping Liu, Li Wang, Abbygail M. Coyle, Erin N. Dankert, Dane K. Hoffman, Stephanie R. Hall, Wei Zhang, Rui Kuang, Anja C. Roden, Aaron S. Mansfield, Luke H. Hoeppner. Molecular mechanisms of non-small cell lung cancer growth and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 873.
Abstract 874: The CRTC1/MAML2 oncogene induces a PGC-1a splice variant that sensitizes mucoepidermoid carcinoma cells to PPARg inhibition
Authors: Musicant Adele M. , Sharma Kshitij P. , Henry Erin C. , Tasoulas Jason , Padilla Ricardo , Sengupta Monideepa , Flaveny Colin , Amelio Antonio L. 
Published: August 2019

Abstract
Mucoepidermoid carcinoma (MEC) is the most common type of malignant salivary gland tumor. MECs frequently exhibit a recurrent t(11;19)(q21;p13) chromosomal translocation that fuses the transcriptional coactivators CRTC1 (CREB-Regulated Transcription Coactivator 1; C1) and MAML2 (Mastermind-Like 2; M2). Though many C1/M2-positive tumors are easily resected, some do progress to advanced, metastatic disease accompanied by poor 5-year survival rates. Thus, it is critical to understand the mechanisms by which C1/M2 drives tumor growth and progression in order to identify therapeutic vulnerabilities. Our lab recently identified a correlation between C1/M2 expression and increased levels of the growth hormone IGF-1. This hormone plays critical roles in the development and homeostasis of normal salivary glands, and its dysregulation has been implicated in several cancers including colon and lung cancers. Interestingly, we demonstrate that IGF-1 is not directly upregulated by C1/M2. Rather, we have discovered a novel C1/M2-driven signaling circuit whereby constitutive CREB activation drives the increased production of a minor PGC-1α (PPARγ Coactivator 1α) splice variant, PGC-1α4, which is responsible for the high IGF-1 levels observed in C1/M2-positive MEC cells. Notably, the PGC-1α4 splice variant is minimally expressed in normal tissues and C1/M2-negative cell lines but is selectively upregulated in C1/M2-positive cell lines. We show that C1/M2 directly binds CREB at the PGC-1α4 promoter to induce expression of this variant, resulting in increased IGF-1 expression. IGF-1 promoter analysis revealed a significant enrichment of PPARγ binding motifs and functional studies confirm that this promoter is regulated by PPARγ. Consequently, we demonstrate that a novel PPARγ inverse agonist is capable of repressing IGF-1 promoter activity and reducing growth and clonogenic potential of C1/M2-positive cell lines that exhibit high PGC-1α4 expression. Collectively, our results reveal a novel therapeutic vulnerability in salivary MEC cells that may extend more broadly to other cancers that exhibit dysregulated CREB activity.
Citation Format: Adele M. Musicant, Kshitij P. Sharma, Erin C. Henry, Jason Tasoulas, Ricardo Padilla, Monideepa Sengupta, Colin Flaveny, Antonio L. Amelio. The CRTC1/MAML2 oncogene induces a PGC-1a splice variant that sensitizes mucoepidermoid carcinoma cells to PPARg inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 874.