bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1446: Glycogen accumulation in aggressive breast cancers under hypoxia
Authors: Altemus Megan Ann , Yates Joel A. , Wu ZhiFen , Bao LiWei , Merajver Sofia D. 
Published: August 2018

Abstract
Cancers utilize diverse metabolic pathways to increase survival and proliferation; therefore, the identification of specific metabolic alterations in aggressive triple-negative and inflammatory breast cancers is a compelling avenue for the development of new treatments. The ability to survive and grow in hypoxia is necessary for breast cancer cells in the center of the tumor mass or in the lymphatic system and other organ environments. Glucose reserves are typically stored in liver and muscle cells as the polysaccharide glycogen. Elevated levels of glycogen have been observed in various cancers, and recent studies have suggested that glycogen metabolism is important for promoting cancer cell survival. We hypothesize that aggressive breast cancers modulate glycogen metabolism to provide nutritional flexibility for proliferation and invasion during cancer progression. To test our hypothesis, we investigated the regulation of glycogen levels in breast cancer and normal-like cells in atmospheric and 1% oxygen. The glycogen content of six breast cancer and one normal-like cell line was measured under normoxic and hypoxic conditions. All cell lines had increased glycogen accumulation under hypoxia, but to varying degrees that did not correlate with receptor status. Expression levels of various genes involved in glycogen synthesis and degradation were determined by qRT-PCR, with no consensus expression pattern between all cell lines. Several key alterations were noted in synthesis and degradation enzymes. We will present an integrative picture of glycogen synthesis and degradation in breast cancer cells. Studies are ongoing to determine the mechanisms through which these changes occur and whether the accumulation of glycogen confers an advantage for continued survival and growth of cancer.
Citation Format: Megan Ann Altemus, Joel A. Yates, ZhiFen Wu, LiWei Bao, Sofia D. Merajver. Glycogen accumulation in aggressive breast cancers under hypoxia [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 1446.
Abstract 145: Pharmacologic inhibition of SIAH2 stabilizes DYRK2 and inhibits survival and self-renewal in chronic myeloid leukemia (CML) leukemic stem cells
Authors: Park Chun Shik , Shen Ye , Lewis Andrew , Suppipat Koramit , Puppi Monica , Tomolonis Julie , Chen Taylor , Pang Paul , Mistretta Toni-Ann , Ma Leyuan , Green Michael , Rau Rachel , Lacorazza Daniel 
Published: August 2018

Abstract
Leukemia stem cells (LSCs) are a rare population able to sustain and recapitulate leukemia through a poorly understood mechanism of self-renewal. Because more than half of patients relapse after the cessation of TKI therapy, it is clear that a cure is not possible with TKIs alone, and LSC-specific drugs are urgently needed to simultaneously eliminate bulk leukemia with TKIs and LSCs. Here we report that KLF4 promotes disease progression in chronic myeloid leukemia (CML) by repressing an inhibitory mechanism in LSCs that can be activated with small molecules. Deletion of the Klf4 gene severely abrogated maintenance of BCR-ABL(p210)-induced CML by impairing survival and self-renewal in LSCs whereas increased self-renewal was observed in hematopoietic stem cells during serial transplantation. Mechanistically, KLF4 represses the Dyrk2 gene and thus loss-of-KLF4 resulted in elevated levels of the DYRK2 kinase in LSCs, which was associated with p53-mediated apoptosis and inhibition of self-renewal through depletion of c-Myc protein. Supporting this model, stabilization of DYRK2 protein, by inhibiting the ubiquitin E3 ligase SIAH2 with vitamin K3, promoted apoptosis in a panel of CML cell lines (K562, KU-812, and KCL-22) by inducing DYRK2 expression. Knocking out the DYRK2 gene in K562 cells by Cas9/CRISPR abrogated cytotoxicity induced by vitamin K3 and the presence of p53 significantly lowered IC50. In vivo treatment of CML mice diminished the number of LSCs evaluated in secondary transplants. In humans, vitamin K3 induced apoptosis in bone marrow cells from CML patients but not in healthy individuals by inducing DYRK2, p53 phosphorylation, and c-Myc depletion; furthermore, vitamin K3 abrogated capacity of CD34+ cells to generate colonies in methylcellulose only in CML. Altogether, our results suggest that DYRK2 is a molecular checkpoint controlling both p53 and c-Myc mediated regulation of survival and self-renewal in CML LSCs that can be activated pharmacologically.
Citation Format: Chun Shik Park, Ye Shen, Andrew Lewis, Koramit Suppipat, Monica Puppi, Julie Tomolonis, Taylor Chen, Paul Pang, Toni-Ann Mistretta, Leyuan Ma, Michael Green, Rachel Rau, Daniel Lacorazza. Pharmacologic inhibition of SIAH2 stabilizes DYRK2 and inhibits survival and self-renewal in chronic myeloid leukemia (CML) leukemic stem cells [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 145.
Abstract 1452: The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ
Authors: Edwards Deanna N. , Ngwa Verra M. , Wang Shan , Shiuan Eileen , Brantley-Sieders Dana , Kim Laura , Reynolds Albert B. , Chen Jin 
Published: August 2018

Abstract
Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing YAP or TAZ substantially reduced the amount of intracellular glutamate through decreased expression of SLC1A5 and GLS, respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both SLC1A5 and GLS contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, EphA2 expression positively correlated with that of YAP and TAZ, as well as that of GLS and SLC1A5. Although high expression or EphA2 predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify therapeutic targets in patients.
Citation Format: Deanna N. Edwards, Verra M. Ngwa, Shan Wang, Eileen Shiuan, Dana Brantley-Sieders, Laura Kim, Albert B. Reynolds, Jin Chen. The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ [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 1452.
Abstract 1453: SLC25A32 sustains cancer cell proliferation by regulating flavin adenine dinucleotide (FAD) metabolism
Authors: Santoro Valeria , Kovalenko Ilya , Vriens Kim , Christen Stefan , Bernthaler Andreas , Haegebarth Andrea , Fendt Sarah-Maria , Christian Sven 
Published: August 2018

Abstract
SLC25A32 is a member of the solute carrier 25 family of mitochondrial transporters. SLC25A32 transports tetrahydrofolate (THF) as well as FAD into mitochondria and regulates mitochondrial one-carbon metabolism and redox balance. While it is known that cancer cells require one-carbon and FAD-dependent mitochondrial metabolism for generation of nucleotides, lipids and for maintenance of redox homeostasis to sustain growth, the role of SLC25A32 in cancer cell survival remains unexplored.
Our results indicate that the SLC25A32 gene is highly amplified in different tumors and that its amplification correlates with increased mRNA expression and with reduced patient survival. SiRNA-mediated knock-down and CRISPR-mediated knock-out of SLC25A32 in cancer cells of different origins, resulted in the identification of sensitive and resistant cells to SLC25A32 inhibition. Mechanistically, tracing of deuterated serine upon SLC25A32 knock-down did not affect the mitochondrial/cytosolic folate flux as measured by Liquid Chromatography coupled Mass Spectrometry (LC-MS). Instead, SLC25A32 inhibition resulted in respiratory chain dysfunction at the FAD-dependent complex II enzyme, induction of Reactive Oxygen
Species (ROS) and depletion of reduced glutathione (GSH), impairing cancer cell proliferation. Moreover, Buthionine sulfoximine (BSO) treatment further sensitized cells to ROS-mediated inhibition of cell proliferation upon SLC25A32 knock-down. Treatment of cells with the FAD precursor riboflavin and with GSH rescued cancer cell proliferation upon SLC25A32 down-regulation.
Our results indicate that inhibition of mitochondrial FAD transport by targeting SLC25A32 has potential clinical applications as a single agent or in combination with approved cancer drugs that lead to increased oxidative stress and reduced tumor growth.
Citation Format: Valeria Santoro, Ilya Kovalenko, Kim Vriens, Stefan Christen, Andreas Bernthaler, Andrea Haegebarth, Sarah-Maria Fendt, Sven Christian. SLC25A32 sustains cancer cell proliferation by regulating flavin adenine dinucleotide (FAD) 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 1453.
Abstract 1454: Glutamate dehydrogenase 1 mediates metabolic reprogramming and promotes tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer
Authors: Kang Sumin , Jin Lingtao , Pan Chaoyun , Chun Jaemoo 
Published: August 2018

Abstract
Although elevated glutaminolysis has been demonstrated in cancer cells, the precise mechanism by which glutaminolysis is exploited to promote tumor metastasis has not been elucidated. Lung cancer frequently metastasizes and is the leading cause of cancer-related death worldwide. Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents in LKB1-deficient lung cancer is still in its infancy. Our recent study reveal that glutamate dehydrogenase 1, upregulated upon detachment via the transcription factor pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product alpha-KG activates CamKK2 by enhancing its substrate AMPK binding and triggers CamKK2-mediated AMPK signaling, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with the small molecule GDH1 inhibitor R162 led to attenuated anoikis resistance and tumor metastasis in an LKB1-deficient lung patient-derived xenograft model. Correlation studies between GDH1 signaling and metastatic cancer progression in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis. This knowledge could be leveraged for the development of effective therapeutic strategies for patients with LKB1-deficient lung cancer.
Citation Format: Sumin Kang, Lingtao Jin, Chaoyun Pan, Jaemoo Chun. Glutamate dehydrogenase 1 mediates metabolic reprogramming and promotes tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung 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 1454.
Abstract 1455: FAK overexpression upregulates glucose metabolism in glioblastoma
Authors: Velpula Kiran Kumar , Pajor Michael , Guda Maheedhara R. , Labak Collin M. , Park Simon , Tsung Andrew J. 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most aggressive brain cancer, afflicting nearly 1 in 6 adult patients with brain tumors. Currently, no effective curative treatment for this CNS neoplasm exists. The high prevalence and dismal prognosis of GBM increases the need to identify novel therapeutic targets. Previous research has suggested that increased expression of focal adhesion kinase (FAK) may play a role in tumor metabolism. Our preliminary data using datamining approach of the TCGA and Oncomine™ databases showed that mRNA levels of FAK correlate with expression levels of the glucose transporter GLUT1. Subsequent mass-spectrometric and immunoprecipitation experiments provided evidence that FAK binds to GLUT1, while immunohistochemistry and immunocytochemistry experiments confirmed their interaction. Western blot analysis using shRNA to silence FAK demonstrated a significant decrease in GLUT1 expression. Cells treated with the same FAK shRNA showed decreased metabolites from anaerobic glycolysis, instead relying on oxygen-dependent metabolism utilizing oxidative phosphorylation for their energy supply. Collectively, we propose that FAK is a viable target in modulating glucose uptake and metabolism in GBM.
Citation Format: Kiran Kumar Velpula, Michael Pajor, Maheedhara R. Guda, Collin M. Labak, Simon Park, Andrew J. Tsung. FAK overexpression upregulates glucose metabolism in glioblastoma [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 1455.
Abstract 1458: TRPM2 modulates neuroblastoma cell survival through Pyk2, CREB and MCU activation
Authors: Hirschler-Laszkiewicz Iwona Malgorzata , Chen Shu-jen , Bao Lei , Wang JuFang , Zhang Xue-Qian , Shanmughapriya Santhanam , Keefer Kerry , Madesh Muniswamy , Cheung Joseph Y. , Miller Barbara A. 
Published: August 2018

Abstract
Transient Receptor Potential Melastatin subfamily member 2 (TRPM2) is highly expressed in many cancers including neuroblastoma. Proline-rich tyrosine kinase 2 (Pyk2) is calcium-sensitive non-receptor tyrosine kinase which enhances cell survival and is activated by calcium influx through TRPM2. Pyk2 also modulates mitochondrial calcium uptake through phosphorylation of the mitochondrial calcium uniporter (MCU), impacting mitochondrial function, and through its effects on CREB, which regulates transcription of MCU. The purpose of this work was to investigate the mechanisms by which TRPM2 regulates cancer cell survival in order to develop new therapeutic strategies based on inhibition of TRPM2. Two models of TRPM2 inhibition were utilized: 1) reducing TRPM2 function in SH-SY5Y cells by expression of the dominant negative construct TRPM2-S, a short isoform of TRPM2, and 2) depletion of TRPM2 expression with CRISPR/Cas9 technology. Treatment with Doxorubicin (Doxo) was used as a model of oxidative stress. Doxorubicin reduced growth of cells in which TRPM2 was inhibited significantly more than control cells. Inhibition of TRPM2 also reduced Pyk2 and CREB expression and activation. Using shRNA technology we showed that Pyk2 mediated reduced expression and activation of CREB and activation of STAT3 in TRPM2 expressing cells. Fractionation experiments showed that depletion of TRPM2 reduced phosphorylation of whole cell and mitochondrial Src and Pyk2 and expression of mitochondrial CREB and MCU. Src has an important role in Pyk2 phosphorylation. In TRPM2 depleted cells, mitochondrial Ca uptake was significantly reduced since both peak mitochondrial calcium uniporter currents and amount of calcium transported (current-time integral) measured in mitoplasts were lower. Wt Pyk2 but not the phospho-deficient mutant Y402F and wt TRPM2 but not the TRPM2 Ca-impermeant mutant E960D, restored viability after Doxo treatment of SH-SY5Y cells in which TRPM2 was inhibited. In conclusion, these results suggest that TRPM2 inhibition leads to reduced viability in neuroblastoma through the Src-Pyk2-CREB-MCU pathway, which plays a key role in regulating mitochondrial function and cellular bioenergetics.
Citation Format: Iwona Malgorzata Hirschler-Laszkiewicz, Shu-jen Chen, Lei Bao, JuFang Wang, Xue-Qian Zhang, Santhanam Shanmughapriya, Kerry Keefer, Muniswamy Madesh, Joseph Y. Cheung, Barbara A. Miller. TRPM2 modulates neuroblastoma cell survival through Pyk2, CREB and MCU activation [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 1458.
Abstract 1459: A mechanism counteracting micronucleation for maintenance of genomic integrity
Authors: Samwer Matthias , Schneider Maximilian W. , Hoefler Rudolf , Schmalhorst Philipp , Jude Julian , Zuber Johannes , Gerlich Daniel W. 
Published: August 2018

Abstract
A hallmark of eukaryotic cells is that they store all their chromosomes in a single nucleus. This is important for the maintenance of genomic integrity, as individual chromosomes packaged into separate micronuclei are prone to massive DNA damage. Micronuclei are characteristic for cancer cells and thought to drive the evolution of cancer genomes. However, the mechanisms normally promoting the packaging of all chromosomes into a single nucleus have remained largely elusive. Animal cells undergo an open mitosis, in which the cell disassembles its nucleus to release a set of individualized chromosomes. At the end of mitosis, cells reassemble a single nucleus around a complete set of chromosomes, utilizing endoplasmic reticulum-derived membranes. How cells restrict nuclear envelope assembly to the surface around the set of anaphase chromosomes is unclear. It has been proposed that the mitotic spindle may help anaphase chromosomes form a continuous surface by bringing them into proximity. Using live cell imaging, we found that the mitotic spindle is not required to form a single nucleus in human cells. We then performed an RNAi screen for spindle-independent factors that are required to shape a single nucleus and identified the protein barrier-to-autointegration factor (BAF). BAF has been previously suggested to contribute to nuclear assembly by linking chromatin to nuclear envelope membranes containing “LEM” domain (Lap2/Emerin/Man1) proteins. However, by RNAi and mutational analysis, we unexpectedly discovered that BAF's LEM-binding activity was dispensable for nuclear assembly in human cells. Instead, we found that BAF's ability to dimerize and cross-bridge distant DNA segments was essential to shape a single nucleus. By probing purified chromatin and recombinant BAF proteins with atomic force microscopy, we found that BAF forms a rigid shell at the chromatin surface, depending on its DNA-DNA cross-bridging activity. In cells, BAF restricted membranes to the surface formed by the set of anaphase chromosomes, thereby preventing the formation of micronuclei. Thus, BAF regulates chromosome mechanics to shape a single nucleus during mitotic exit.
Citation Format: Matthias Samwer, Maximilian W. Schneider, Rudolf Hoefler, Philipp Schmalhorst, Julian Jude, Johannes Zuber, Daniel W. Gerlich. A mechanism counteracting micronucleation for maintenance of genomic integrity [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 1459.
Abstract 1462: The oncogene MYC induces chromosomal instability through dysregulating mitotic progression evoking a dependency on TPX2
Authors: Rohrberg Julia , Corella Alexandra , Taileb Moufida , Jokisch Marie-Lena , Camarda Roman , Balakrishnan Sanjeev , Zhou Alicia , Goga Andrei 
Published: August 2018

Abstract
More than 70% of common solid tumors are aneuploid. Aneuploidy has been implicated in tumorigenesis for decades. A direct cause of aneuploidy is chromosomal instability (CIN) that fuels tumor evolution by providing a heterogeneous subpopulation of cells that contributes to the lethal outcome of cancer, metastasis, therapeutic failure, and drug resistance. The oncogene c-MYC is overexpressed in many cancers and has been shown to induce structural and numerical chromosomal aberrations and aneuploidy. While the role of MYC in overcoming the G1/S checkpoint is well established, the role of MYC in altering mitotic dynamics and eliciting CIN remains poorly understood. Here, we identify a direct influence of increased MYC expression on mitotic progression and spindle assembly. We observe MYC-dependent microtubule nucleation and polymerization defects in mitosis. MYC overexpression induces altered spindle morphology promoting chromosome segregation defects resulting in micronuclei formation, CIN and aneuploidy. Importantly, attenuation of MYC expression reverses the mitotic defects observed, even in established tumor cell lines, implicating an ongoing role for MYC in the persistence of a CIN phenotype in tumors. Gene expression data reveal that MYC regulates numerous genes involved in mitosis, kinetochore function and microtubule behavior. We performed a screen to identify microtubule regulators required for the survival of MYC overexpressing cells. MYC overexpressing cells are reliant on high TPX2 expression, a master microtubule regulator. High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in MYC high cells, while TPX2 depletion attenuates cell viability and tumor growth in vivo. Our data suggest that TPX2 is a transcriptional target of MYC. We postulate that high levels of TPX2 are required to tolerate mitotic stress induced by MYC. TPX2 compensates for impaired mitotic progression and prevents the development of physiologically intolerable levels of CIN. High levels of TPX2 might be required for tumors with oncogene-induced mitotic stress to faithfully proceed through mitosis providing an explanation for the abundant upregulation of TPX2 in cancer. Thus, we describe a conditional role for MYC in altering spindle assembly and dynamics, resulting in a dependency on TPX2 for tumor survival.
Citation Format: Julia Rohrberg, Alexandra Corella, Moufida Taileb, Marie-Lena Jokisch, Roman Camarda, Sanjeev Balakrishnan, Alicia Zhou, Andrei Goga. The oncogene MYC induces chromosomal instability through dysregulating mitotic progression evoking a dependency on TPX2 [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 1462.