bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 24: Extracellular HMGA1 promotes tumor invasion and metastasis in breast cancer
Authors: Méndez Olga , Peg Vicente , Salvans Candida , Pujals Mireia , Fernández Yolanda , Abasolo Ibane , Perez Jose , Matres Ana , Tabernero Josep , Cortés Javier , Arribas Joaquín , Villanueva Josep 
Published: August 2018

Abstract
The recent in-depth study of the cancer secretome suggests that a fraction of the intracellular proteome might be playing alternative roles in the extracellular space during tumorigenesis through its unconventional secretion. A proteomic study aimed at evaluating the role of unconventional protein secretion in the context of tumor invasion led us to investigate the high mobility group A1 (HMGA1) chromatin-binding protein whose overexpression has been correlated with high-grade carcinomas and reduced patient-survival. Here we show that HMGA1 is not only oversecreted in invasive breast tumor cells, but its blockage with specific antibodies in the extracellular space impairs tumor cell migration and invasion. The invasive phenotype caused by extracellular HMGA1 (eHMGA1) is dependent on ERK1/2 signaling and a blocking-Ab against eHMGA1 decreases pERK and re-localizes HMGA1 to the nucleus concomitantly to the loss of invasion capacity. Remarkably, pre-treatment of invasive breast tumor cells with an HMGA1-blocking Ab reduces their metastatic ability in an orthotopic breast cancer xenograft model. HMGA1 also shows a cytoplasmic localization in primary human triple-negative breast cancer (TNBC) tumors that developed distant metastasis while displaying a nuclear localization in TNBC tumors that did not progress to metastatic disease. Thus, eHMGA1 could be a novel drug target in aggressive breast cancer and a biomarker predicting the onset of distant metastasis.
Citation Format: Olga Méndez, Vicente Peg, Candida Salvans, Mireia Pujals, Yolanda Fernández, Ibane Abasolo, Jose Perez, Ana Matres, Josep Tabernero, Javier Cortés, Joaquín Arribas, Josep Villanueva. Extracellular HMGA1 promotes tumor invasion and metastasis in breast 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 24.
Abstract 2409: The effect of heme on mitochondrial biogenesis and function of NSCLC cells
Authors: Sohoni Sagar Shashikant , Vidal Chantal , Zhang Li 
Published: August 2018

Abstract
Heme is a central molecule for mitochondrial function and for many processes involved in oxygen utilization. Heme serves as a prosthetic group or a cofactor for a number of oxidative phosphorylation enzymes and other oxygen-utilizing hemoproteins. Heme also directly regulates the synthesis, translocation, and assembly of these enzyme complexes. Most, if not all, human cells can synthesize and uptake heme from the circulation. A number of epidemiologic studies have shown that high heme intake is associated with increased risk of cancer, including lung cancer. To assess the status of heme metabolism in lung cancer cells, we performed a series of experiments in non-small cell lung cancer (NSCLC) cell lines and compared the results with an immortalized normal lung cell line, HBEC30KT. We observed significant increase in rates of heme synthesis and heme uptake in NSCLC cells compared to HBEC30KT. Previous studies carried out in our lab showed intensified mitochondrial respiration and increased levels of heme as well as hemoproteins in NSCLCs. NSCLCs were also found to exhibit significantly high expressions of proteins involved in mitochondrial biogenesis such as SIRT-1, PGC1α, NRF-1, NRF-2, and TFAM. Expression levels of these proteins correlate with oxygen consumption and total heme content in NSCLCs, suggesting a possibility of role of heme in mitochondrial biogenesis. Immunofluoresence studies showed that heme depletion and add-back significantly affected localization and expression levels of these proteins. Studies are currently under way to determine how heme depletion affects the interactions of various transcription factors involved in mitochondrial biogenesis and function.
Citation Format: Sagar Shashikant Sohoni, Chantal Vidal, Li Zhang. The effect of heme on mitochondrial biogenesis and function of NSCLC 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 2409.
Abstract 2419: Lipid droplets promote glioblastoma cell growth through maintaining cholesterol homeostasis mediated by autophagy
Authors: Geng Feng , Cheng Xiang , Cheng Chunming , Chakravarti Arnab , Guo Deliang 
Published: August 2018

Abstract
Lipid droplets (LDs) have been studied as the major storage site of neutral lipids for decades, especially in the progression of metabolic diseases. Recently, the functions of LDs in cancers have begun to gain significant attention. Here, we provide evidence that LDs promote glioblastoma (GBM) cell growth through autophagy mediated maintenance of cholesterol homeostasis. Our data showed that LDs in tumor tissues from GBM patients are engulfed by autophagic vacuoles and lysosomes. Cellular cholesterol deprivation or removal of plasma membrane cholesterol by methyl-β-cyclodextrin (MβCD) activates autophagy to hydrolyze LDs to support GBM cell survival, whereas inhibition of autophagy blocks transportation of cholesterol to plasma membrane, leading to cell death. Fluorescence imaging reveals direct trafficking of LD-stored cholesterol to the plasma membrane through autophagic liberation. Our data demonstrate that LDs serve as cholesterol reservoir for GBM cell growth, suggesting that targeting LD-autophagy-cholesterol homeostasis metabolic pathway represents a potential means to treat GBM and other malignancies.
Citation Format: Feng Geng, Xiang Cheng, Chunming Cheng, Arnab Chakravarti, Deliang Guo. Lipid droplets promote glioblastoma cell growth through maintaining cholesterol homeostasis mediated by autophagy [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 2419.
Abstract 242: Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic cancer
Authors: Walsh Naomi , Zhang Han , Hyland Paula L. , Yang Qi , Mocci Evelina , Zhang Mingfeng , Childs Erica J. , Wang Zhaoming , Chanock Stephen , Hartge Patricia , Hoover Robert , Kraft Peter , Li Donghui , Jacobs Eric J. , Petersen Gloria M. , Wolpin Brian M. , Risch Harvey A. , Amundadottir Laufey T. , Yu Kai , Klein Alison P. , Stolzenberg-Solomon Rachael Z. 
Published: August 2018

Abstract
Objective Genome-wide association studies (GWAS) identify associations of individual SNPs with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants has been shown for many disorders to be a powerful tool in discovering novel networks of susceptibility genes. Design We have conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product (sARTP) method to identify novel gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDA) in 9,040 cases and 12,495 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes identified in PDA-associated gene sets and pathways. Results We identified 14 gene sets and pathways associated with PDA at FDR &lt; 0.05. Five of the strongest signals (P-value ≤ 1.3x10-5 Bonferroni corrected) were in genes from KEGG maturity onset diabetes of the young, Reactome regulation of beta cell development, Biocarta role of epidermal growth factor (EGF) receptor transactivation by G-protein-coupled receptors in cardiac hypertrophy pathway, Nikolsky breast cancer chr17q11-q21 amplicon gene set, and Pujana ATM Pearson correlation coefficient (PCC) network gene set. We identified and validated rs876493 and three correlated SNPs (PGAP3) and rs3124737 (CASP7) as eQTLs in two normal derived pancreas tissue datasets. Conclusion Our agnostic gene set and pathway analysis integrated with functional annotation and eQTL analysis provides novel insight into genes and pathways that may be biologically relevant for risk of PDA.
Citation Format: Naomi Walsh, Han Zhang, Paula L. Hyland, Qi Yang, Evelina Mocci, Mingfeng Zhang, Erica J. Childs, Zhaoming Wang, Stephen Chanock, Patricia Hartge, Robert Hoover, Peter Kraft, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Kai Yu, Alison P. Klein, Rachael Z. Stolzenberg-Solomon. Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic 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 242.
Abstract 2423: Hypoxia regulates tumor cell invasiveness through altered glycosylation
Authors: Greville Gordon , Llop Esther , Miró Rosa Peracaula , McCann Amanda , Rudd Pauline M. , Saldova Radka 
Published: August 2018

Abstract
Glycosylation, one of the most fundamental post-translational modifications, is altered in many cancers. These alterations have been proven to impact on the progression of the tumor cell and promote survival. In literature published over the last half century, it is obvious there is a clear link between (a) chemo-resistance and hypoxia (b) hypoxia and epigenetics and more recently (c) glycosylation and epigenetics. We aim to bring these paradigms together with the remit of offering a more complete story and opening up new avenues of approach for the detection, diagnosis and treatment of breast and ovarian cancer.
Ovarian and breast cancer cells were exposed to differential hypoxic conditions (0.5%, 1.0%, 2.0%) and normoxia. Firstly, we compared the methylation status of hypoxia exposed cells to the normoxic controls. A combination of hydrophilic interaction liquid chromatography (HILIC) and statistical analyses allowed comparisons of the secreted N-glycans from cells exposed to differential hypoxic conditions. Western blots assessed apoptosis, senescence, autophagy and epithelial to mesenchymal transition. The OrisTM migration assay assessed the migration of the cells pre- and post-differential hypoxic exposure. RT-qPCR was used to measure gene expression of appropriate glycosyltransferases and possible transcription factors (TFs) in these samples to determine any associations with changes seen in N-glycosylation.
There were non-significant trends observed between the percentage oxygen that the cells were exposed to and resultant changes seen in branching and sialylation on secreted N-glycans from the breast and ovarian cancer cell lines. While only some of these changes could be explained by RT-qPCR data, GATA2/3 transcripts, identified in-silico as possible TFs, have been shown to significantly correlate with ST3GAL4 and MGAT5 glycosyltransferases, respectively. Hypoxia exposed cells also displayed increased migration with a greater effect seen in the 0.5% hypoxia exposed samples.
The GATA2 and GATA3 transcription factors are gaining popularity in recent years, with links to cancer stage, increased invasiveness and as possible therapeutic targets. Our recent data shows a strong correlation between GATA2 and GATA3 and the levels of glycosyltransferases involved in branching and sialyation. These glycan changes are known to be strongly involved in cancer cell survival and metastases. Here for the first time we may have a possible mechanism of action linking GATA2 and 3 and invasiveness of breast and ovarian cancer cells.
Citation Format: Gordon Greville, Esther Llop, Rosa Peracaula Miró, Amanda McCann, Pauline M. Rudd, Radka Saldova. Hypoxia regulates tumor cell invasiveness through altered glycosylation [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 2423.
Abstract 2429: HIF-1α repressed glycerol-3-phosphate shuttle to reduce oxidative stress in liver cancer
Authors: ZHANG Shuo , LAI Robin Kit-Ho , CHIU David Kung-Chun , XU Iris Mingjing , TSE Aki Pui Wah , WONG Chun-Ming , NG Irene Oi Lin , WONG Carmen Chak Lui 
Published: August 2018

Abstract
Liver cancer is the fifth most prevalent and third most common cancer globally. Hepatocellular carcinoma (HCC), arises from hepatocytes, accounts for more than 80% of liver cancer. HCC cells undergo extensive metabolic rewiring to support their uncontrolled growth. HCC cells encounter extremely high level of oxidative stress which is mostly generated in the electron transport chain. Reactive oxygen species (ROS) rapidly accumulate in the electron transport chain (ETC) during hypoxia due to inadequate electron transfer to O2 in the ETC. The glycerol phosphate (GP) shuttle plays an important role to transfer electron source (NADH) from cytoplasm to mitochondria to initiate the ETC. The GP shuttle is mediated by glycerol 3 phosphate dehydrogenase (GPD) which converts dihydroxyacetone phosphate to glycerol 3 phosphate (G3P) through the oxidation of NADH to NAD+. This contributes to ATP production in the mitochondria. Here, we reported that hypoxia-inducible factor 1 (HIF-1) acts as a transcriptional repressor instead of an activator to suppress transcription of an important ETC component of the glycerol phosphate shuttle (GPD) to reduce activity of the GP shuttle, thereby reducing oxidative stress. GPD expression was significantly reduced under hypoxic condition. Surprisingly, knockout, knockdown, or inhibition of HIF-1 restored GPD expression in hypoxia. GPD expression was significantly under-expressed in tumorous as compared to non-tumorous liver tissues in 91 HCC patients of our center by 2.67 fold. TCGA database containing 49 HCC patients echoed with our in-house data. Downregulation of GPD was associated with poor cellular differentiation and overall survival in HCC patients. Stable overexpression of GPD1 in multiple HCC cell lines increased the levels of G3P as well as NAD+, which is crucial to lactate dehydrogenase (LDHA) activity. GPD overexpression altered mitochondrial activity, ROS levels, and suppressed HCC cell proliferation. Taken together, this study showed that the HIF-1 negatively controls key component of the GP shuttle to maximize HCC growth.
Citation Format: Shuo ZHANG, Robin Kit-Ho LAI, David Kung-Chun CHIU, Iris Mingjing XU, Aki Pui Wah TSE, Chun-Ming WONG, Irene Oi Lin NG, Carmen Chak Lui WONG. HIF-1α repressed glycerol-3-phosphate shuttle to reduce oxidative stress in liver 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 2429.
Abstract 2432: The genomic consequences of tumor hypoxia in human cancers
Authors: Bhandari Vinayak , Espiritu Shadrielle M. , Liu Lydia Y. , Lalonde Emilie , Yamaguchi Takafumi N. , Heisler Lawrence E. , Livingstone Julie , Huang Vincent , Shiah Yu-Jia , Sabelnykova Veronica Y. , Yousif Fouad , Chua Melvin L. , Fraser Michael , Kwast Theodorus van der , Boutros Paul C. , Bristow Robert G. 
Published: August 2018

Abstract
Introduction: Localized prostate cancers are classified into risk-groups using clinical measurements like grade and stage to inform treatment decisions. However, these groupings are imprecise: ~30% of intermediate-risk patients suffer relapse of their disease despite precision image-guided radiotherapy or radical prostatectomy. One reason for this variability in response to treatment is the underlying cellular and molecular heterogeneity of tumors. Prostate tumor cells exist within a microenvironment characterized by gradients of oxygen levels and prostate tumors with low levels of oxygen (hypoxia) have poor clinical outcomes.
Methods and Results: To understand the correlates of hypoxia in cancer we conducted a pan-cancer analysis of copy number alterations (CNAs) and single nucleotide variants (SNVs) across 19 cancer types. We measured hypoxia using multiple mRNA-based signatures and discovered numerous CNAs and SNVs enriched or depleted in hypoxic tumors, highlighting the role of hypoxia in shaping the genomic landscape of multiple tumor types. Next, we examined 548 patients with localized prostate cancer and statistically assessed the association of hypoxia with CNAs, SNVs, genomic rearrangements, focal genomic events (i.e. kataegis, chromothripsis), telomere length, clinical indices (i.e. grade, stage) and subclonal architecture. Tumor hypoxia is associated with specific CNAs and SNVs in prostate cancer driver genes. To translate these findings into a biomarker for prostate cancer precision medicine, we integrated tumor microenvironmental data with genomic and pathological information to stratify patients into distinct prognostic groups.
Impact: These data suggest that the aggressiveness of cancers is driven by the interplay of the tumor microenvironment and its genomic mutational profile.
Citation Format: Vinayak Bhandari, Shadrielle M. Espiritu, Lydia Y. Liu, Emilie Lalonde, Takafumi N. Yamaguchi, Lawrence E. Heisler, Julie Livingstone, Vincent Huang, Yu-Jia Shiah, Veronica Y. Sabelnykova, Fouad Yousif, Melvin L. Chua, Michael Fraser, Theodorus van der Kwast, Paul C. Boutros, Robert G. Bristow. The genomic consequences of tumor hypoxia in human cancers [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 2432.
Abstract 2434: Regulation of HIF1a stability by an antisense RNA
Authors: Huang Xin , Huang Huang 
Published: August 2018

Abstract
Hypoxia is a hallmark of solid tumors. Hypoxia-inducible factors (HIFs) are the main transcriptional factor that regulate the cellular response to hypoxic stress. HIFs are heterodimers consisting of an oxygen-sensitive alpha subunit (HIFα) and a constitutively active beta subunit (HIF1β, also called aryl hydrocarbon receptor nuclear translocator, ARNT). Among the three homologous HIFα genes, HIF1α, HIF2α, and HIF3α, the functions of HIF1α and HIF2α are best characterized. HIF1α is ubiquitously expressed in essentially all tissue types, while HIF2α expression is more tissue specific. Under normoxia, HIFα is hydoxylated by prolyl-4-hydroxylases (PHDs), targeting it for proteasome destruction mediated by the von Hippel Lindau (VHL) protein, an E3 ubiquitin ligase. Under hypoxic conditions, the activity of PHDs decreases and HIFα is stabilized and forms a dimer with HIF1β. The HIFα/HIF1β dimer is then translocated into the nucleus and binds specifically to the promoters of a large number of target genes involved in adaptation and protection against low oxygen conditions. It is well known that HIFα is stabilized by acute hypoxia and its level decreases under prolonged hypoxic conditions. However, the mechanism remains unknown. Now, we have identified an antisense RNA that regulates the interaction between HIFα and VHL. The induction of the anitsense RNA is responsible for the regulation of HIFα stability under prolonged hypoxia. Our study revealed a novel mechanism regulating HIFα pathway.
Citation Format: Xin Huang, Huang Huang. Regulation of HIF1a stability by an antisense RNA [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 2434.
Abstract 2436: Anti-cancer effect by combination treatment of CDK and HSP90 inhibitors through HIF1α inhibition
Authors: Zhao Shuai , Zhou Lanlan , Dicker David T. , El-Deiry Wafik S. 
Published: August 2018

Abstract
Hypoxia-inducible factor 1α (HIF1α) is the main mediator of the adaptive response to intra-tumoral hypoxia. HIF1α overexpression contributes to tumor angiogenesis, cancer cell survival and metastasis. Thus, targeting HIF1α provides new opportunities for cancer therapy. We have previously shown that cyclin-dependent kinase 1 (CDK1) stabilizes HIF1α through direct phosphorylation of its Ser668 residue in a Von Hippel-Lindau (VHL)-independent or p53-independent manner both under hypoxia and at G2/M under normoxia (Warfel et al., Cell Cycle, 2013). Because heat shock protein 90 (HSP90) is a VHL-independent HIF1α stabilizer, we hypothesized CDK and CDK inhibitor effects in the stabilization/destabilization mechanism. We found that CDK1 inhibition disrupts the interaction between HSP90 and HIF1α. Moreover, administration of the CDK1 inhibitor, Ro-3306, partially reversed a heat shock (40°C) response dependent increase in the level of HIF1α, which suggests that CDK1 activity may contribute to HSP90-mediated HIF1α stabilization. Combination treatment with both HSP90 inhibitor and CDK1 inhibition/knockdown decreased HIF1α level more robustly than either single treatment. Dual inhibition of CDK1 and HSP90 not only synergistically decreased cell viability but also remarkably reduced colony formation of HCT116 colon cancer cells. Previously we have also shown that similar to CDK1, CDK4 plays a role in HIF1α stabilization as well. This led us to investigate the effect of CDK4/HSP90 dual inhibition on colorectal cancer cells. The combination treatment of CDK4 knockdown/inhibition and HSP90 inhibition reduced the level of HIF1α in various cancer cell lines (e.g., colorectal, glioblastoma, prostate cancers). The FDA-approved CDK4 inhibitor palbociclib along with ganetespib synergistically inhibited cell viability in SW480 colon cancer cells under hypoxia or normoxia. No reduction in cell viability was noted in WI38 normal cells under normoxia at similar concentrations. In addition, we tested the therapeutic potential of the dual CDKi/HSP90i therapy in vivo. The combination treatment of palbociclib and ganetespib inhibited tumor growth in the HT29 colon cancer cell xenograft mouse model at relatively low doses. Immunohistochemistry staining of the tumor samples revealed higher levels of apoptosis, lower levels of VEGF expression and reduced microvessel formation in the combination treatment group. Our findings provide a compelling rationale for a therapeutic strategy to target HIF1α through the combination of CDK and HSP90 inhibitors in cancer therapy.
Citation Format: Shuai Zhao, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry. Anti-cancer effect by combination treatment of CDK and HSP90 inhibitors through HIF1α inhibition [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 2436.