bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B06: Complex requirement of YAP and TAZ in gastrointestinal development and tumorigenesis
Authors: Cotton Jennifer L. , Li Qi , Ma Lifang , Ip Tony , Johnson Randy , Mao Junhao
Published: May 2016

YAP and TAZ are the major intracellular mediators of Hippo signaling in mammals; however, the precise function of YAP/TAZ in gastrointestinal development and tumorigenesis remains poorly understood. By specific removal of YAP/TAZ from the developing endoderm and gastrointestinal tract, we find that YAP/TAZ are dispensable for Wnt signal transduction and normal gastrointestinal epithelial differentiation, but act as the direct TCF4 targets and downstream effectors during epithelial transformation. Surprisingly, our loss- and gain-of-function genetic analyses identify an essential role for YAP/TAZ in the gastrointestinal mesenchyme as a molecular switch to coordinate growth and differentiation. We find that YAP/TAZ are required for the expansion of the primitive progenitor populations critical for mesenchymal growth. However, persistent YAP activation inhibits the induction of the smooth muscle lineage, and YAP/TAZ down-regulation during later development is essential for Hedgehog signaling-induced differentiation of smooth muscle cells. Taken together, our studies uncover a complex requirement of YAP/TAZ in the gastrointestinal tract and demonstrate the functional interplays among key signaling pathways during gastrointestinal development and tumorigenesis.

Citation Format: Jennifer L. Cotton, Qi Li, Lifang Ma, Tony Ip, Randy Johnson, Junhao Mao. Complex requirement of YAP and TAZ in gastrointestinal development and tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B06.
Abstract B08: Altering cellular differentiation and energy metabolism by the mTORC1 inhibitor NPRL2
Authors: Dutchak Paul A. , Terpack SandiJo , Tu Benjamin P.
Published: May 2016

Nitrogen permease regulator-like 2 (NPRL2) is a component of an evolutionarily conserved complex that inhibits mTORC1 (mechanistic Target Of Rapamycin Complex 1) in response to amino acid insufficiency. The NPRL2 complex functions as a GTPase activating protein against the RAG proteins, which are located on the lysosomal surface and stimulate mTORC1 activity when bound to GTP. Since the loss of NPRL2 expression is frequently associated with different types of cancers, including renal and lung, our aim is to investigate the biological function of NPRL2 in vivo and determine how this pathway can contribute to cancer growth. Previous data from our lab show that NPRL2 is required for mouse viability and that its absence significantly compromises fetal liver hematopoiesis in embryos with defective lysosomal processing of vitamin B12 and methionine/SAM homeostasis contributing to the phenotype. Here we show that loss of NPRL2 in muscle alters the differentiation of fiber-types, leading to increased size and number of glycolytic muscle fibers in the mice. Consistent with this phenotype, the NPRL2 muscle specific knockout mice show a sprinting phenotype and increased glucose utilization. These findings demonstrate that NPRL2 is able to regulate cellular differentiation patterns potentially by altering cellular methylation and represents a genetic link between amino acid metabolism and carbohydrate utilization, two hallmarks that are frequently altered in cancer.

Citation Format: Paul A. Dutchak, SandiJo Terpack, Benjamin P. Tu. Altering cellular differentiation and energy metabolism by the mTORC1 inhibitor NPRL2. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B08.
Abstract B13: ETC-159 is a novel PORCN inhibitor effective for treatment of Wnt-addicted genetically defined cancers
Authors: Madan Babita , Ke Zhiyuan , Harmston Nathan , Petretto Enrico , Hill Jeffrey , Keller Thomas H. , Lee May Ann , Matter Alex , Virshup David M.
Published: May 2016

Pathologic expression of Wnts is found in cancers, fibrosis and other diseases, hence there is considerable interest in blocking Wnt signaling to achieve therapeutic benefit. Post-translational palmitoleation of Wnts at a highly conserved serine residue is essential for their secretion and function. We have pursued a strategy to block all Wnt-dependent pathways concomitantly using a small molecule inhibitor of the enzyme PORCN that is required for Wnt O-palmitoleation. As Wnt pathway inhibitors advance to clinical trials, the paucity of well-defined biomarkers makes it challenging to monitor response to therapeutics.

We have developed a novel PORCN inhibitor ETC-159, which has remarkable efficacy in pre-clinical models of RNF43-mutant pancreatic and ovarian cancers and RSPO3-translocation bearing colorectal cancer patient derived xenografts. ETC-159 reverses Wnt dependent pathology by promoting cellular differentiation. Consistent with the role of Wnt/β-catenin signaling in regulation of diverse cellular functions, RNA sequencing of these ETC-159 sensitive, Wnt driven cancers has revealed significant remodeling of the transcriptome on treatment with ETC-159 with a decrease of cell cycle, stem cell, and proliferation genes and an increase in differentiation markers. Our studies show that coordinate regulation of NOTUM and AXIN2 gene expression may be a useful predictor of sensitivity to PORCN inhibitors. NOTUM is a secreted protein and its levels in serum correlate with tumor growth. Notum has potential to be a pharmacodynamic biomarker that will reflect a response to PORCN and other Wnt pathway inhibitors.

Citation Format: Babita Madan, Zhiyuan Ke, Nathan Harmston, Enrico Petretto, Jeffrey Hill, Thomas H. Keller, May Ann Lee, Alex Matter, David M. Virshup. ETC-159 is a novel PORCN inhibitor effective for treatment of Wnt-addicted genetically defined cancers. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B13.
Abstract IA01: Wnt signaling stem cell control and cancer
Authors: Nusse Roel
Published: May 2016

Our laboratory is interested in the growth, development and integrity of animal tissues, with a focus on stem cells. Wnt signaling is widely implicated in stem cell control, as a mechanism to regulate the number of stem cells in tissues, Using various cell labeling methods, we have described novel populations of stem cells in various tissues, including in the liver. In that tissue, we found that hepatocytes that reside in the pericentral domain of the liver demonstrate stem cell behavior. Although these cells are functional hepatocytes, they are diploid and thus differ from the mostly polyploid mature hepatocyte population. They are active in homeostatic cell replacement and therefore distinct from oval cells, which require injury for their induction. Adjacent central vein endothelial cells provide the essential source of Wnt signals for the hepatocyte stem cells and thereby constitute the liver stem cell niche. It is noteworthy that liver cancer is often characterized by loss of function mutations in negative components of the Wnt pathway, including Axin and APC. We suggest that pericentral hepatocyte stem cells, normally controlled by a paracrine Wnt signal, are precursors to liver cancer.

Citation Format: Roel Nusse. Wnt signaling stem cell control and cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA01.
Abstract IA07: The effect of cell of origin on GBM phenotype
Authors: Parada Luis F.
Published: May 2016

Current thinking about solid tumor biology is largely influenced by analysis of the large data sets afforded by modern genomic capabilities. In GBM, classification of tumors into four categories (proneural, neural, mesenchymal, and classic) relies on differential transcriptional profiles coupled with copy numbers, and mutational profiles. These approaches for example, imply EGFR receptor as a major driver of Classic sub-type whereas NF1 mutations are preferentially found in mesenchymal subtypes. Functional evidence that these molecular categories indeed reflect biologically different tumors remains to be proved. We have generated mouse models of GBM by driving loss of function of in the NF1, p53 and Pten tumor suppressors. We find that two phenotypically and biologically different GBMs emerge that reflect tumor initiation different adult CNS progenitor populations. Thus, in a mouse model, distinct progenitor cell populations dictate different tumors created by mutation in identical drivers.

Citation Format: Luis F. Parada. The effect of cell of origin on GBM phenotype. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA07.
Abstract A44: Expression of metabolic genes is associated with prognosis in breast cancer
Authors: Aiderus Abdul Aziz Bin , Black Michael A. , Dunbier Anita K.
Published: May 2016

Breast cancer is the most common malignancy and is the second leading cause of cancer-related death in American women. Approximately 75% of breast tumors express the oestrogen receptor, which can be targeted for with selective oestrogen receptor modulator such as tamoxifen, or by blocking oestrogen synthesis using aromatase inhibitors. However, approximately a quarter of patients treated for at least five years relapse with the disease within a decade. Many transcriptome studies have been conducted on breast tumor samples with clinical data to generate gene signatures predictive of treatment outcome. While several signatures have been reported, these features tend to be correlated with proliferation and give little information about the underlying tumor biology.

An emerging hallmark of cancer is the reprogramming of metabolic networks to meet the demand required for rapid growth of a tumor. Tumors are generally highly glycolytic to meet their energetic requirements, as well as to provide substrates for anabolic reactions necessary for cell growth. However, perturbations in other metabolic pathways that are essential for tumor development and growth remain poorly understood. In this study, we sought to identify and characterise molecular features associated with metabolism that are significantly correlated with breast cancer patient outcome. To achieve this, we performed Cox regression analysis on a training set of microarray gene expression data of 973 oestrogen-receptor positive breast tumors. To identify functional enrichment for the molecular features associated with disease-free survival, gene set enrichment analysis was performed. This analysis revealed a 19-gene signature involved in fatty acid metabolism that showed higher expression to be correlated with good prognosis in the training data (multivariate hazard ratio = 0.51, log-rank p = 2.23e-10). The prognostic performance of this signature was validated on an independent dataset (n=654, multivariate hazard ratio = 0.66, log-rank p = 6.51e-5). Using the online KMplotter software, the fatty acid metabolism signature was found to also be prognostic in both lung cancer (n=1926, univariate hazard ratio = 0.58, log-rank p = 1.1e-16) and gastric cancer (n=593, univariate hazard ratio = 0.73, log-rank p = 0.0012).

Based on our bioinformatic findings, we hypothesise that tumors with lowered fatty acid metabolism are more likely to exhibit invasive properties. Current work is focused on understanding how modulating fatty acid metabolism affects tumor biology, and may present a therapeutically tractable process that can be targeted with existing drugs.

Citation Format: Abdul Aziz Bin Aiderus, Michael A. Black, Anita K. Dunbier. Expression of metabolic genes is associated with prognosis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A44.
Abstract A54: Changes in fatty acid profile indicate a chemo-preventive response to navy bean extract in an inflammation-associated colorectal cancer mouse model
Authors: Perera Thushanthi H. , Young Matthew R. , Saud Shakir M. , Dextras Christopher R. , Jones-Hall Yava L. , Karoly Edward D. , Sampey Brante P. , Kim Young S. , Colburn Nancy H. , Bobe Gerd
Published: May 2016

Introduction: Consumption of dry beans and their fractions decrease colorectal neoplasia; however, the underlying molecular mechanisms are unclear. Aim of the study was to identify response indicators of dietary attenuation of colorectal tumorigenesis using metabolic profiling.

Methods: The study had a 2 x 2 factorial design. After being either induced or not with azoxymethane/dextran sodium sulfate (AOM/DSS), male FVB/N mice were fed an AIN93G diet containing either 0 (Control) or 10% navy bean ethanol extract (BE) for 6 weeks. Colon tissue was collected and analyzed for colitis, aberrant cell proliferation, and tumor, whereas serum, feed, and fecal samples were analyzed for metabolite levels.

Results: Dietary BE attenuated AOM/DSS-induced chronic colitis, aberrant epithelial cell proliferation, fecal blood (heme), and tumorigenesis (-40%; P=0.02) in the colon. Similar changes were observed for fecal medium-chain fatty acids (hexanoate, octonoate) and plant phenolics (vanillate) and serum markers of fatty acid oxidation (carnitine, hexanoylcarnitine), and the pentose phosphate pathway (sedophetulose-7-phosphate). Moreover, dietary BE increased fecal markers of apoptosis (ribose, uracil, pseudouridine, xanthine, hypoxanthine) and attenuated the AOM/DSS-induced decrease in serum glycerophosphocholine.

Conclusions: Dietary BE may inhibit survival and proliferation of premalignant colorectal epithelial cells by promoting fatty acid oxidation and resolving inflammation.

Citation Format: Thushanthi H. Perera, Matthew R, Young, Shakir M. Saud, Christopher R. Dextras, Yava L. Jones-Hall, Edward D. Karoly, Brante P. Sampey, Young S. Kim, Nancy H. Colburn, Gerd Bobe. Changes in fatty acid profile indicate a chemo-preventive response to navy bean extract in an inflammation-associated colorectal cancer mouse model. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A54.
Abstract A65: IACS-10759: A novel OXPHOS inhibitor that selectively kills tumors with metabolic vulnerabilities
Authors: Protopopova Marina , Bandi Madhavi , Sun Yuting , Bardenhagen Jennifer , Bristow Christopher , Carroll Christopher , Chang Edward , Feng Ningping , Gay Jason , Do Mary Geck , Greer Jennifer , Konopleva Marina , Matre Polina , Kang Zhijun , Liu Gang , Muller Florian , Lofton Timothy , McAfoos Timothy , Smith Melinda , Theroff Jay , Han Jing , Wu Yuanqing , Chin Lynda , Draetta Giulio , Jones Philip , Toniatti Carlo , Francesco M. Emilia Di , Marszalek Joseph R.
Published: May 2016

Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks for rapid growth. Metabolic vulnerabilities caused by inactivation of glycolysis render tumor cells highly dependent on OXPHOS, and represent a therapeutic opportunity. Through an extensive medicinal chemistry campaign, we have identified IACS-10759 as a potent inhibitor of complex I of OXPHOS. IACS-10759 effectively inhibits ATP production and oxygen consumption in isolated mitochondria, and inhibits the conversion of NADH to NAD+ in immunoprecipitated complex I in low nM range. The exact subunit that IACS-10759 binds to is under investigation. Importantly, IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species, and shows significant efficacy in multiple tumor indications both in vitro and in vivo. Specifically, in a glycolysis-deficient xenograft model, IACS-10759 causes robust tumor regression, but has no effect in the same model when glycolysis is restored. In addition, in AML where tumor cells have been shown to be highly OXPHOS-dependent, IACS-10759 robustly suppresses cell growth and induces apoptosis in both primary AML samples and cell lines in vitro, but not in normal patient-derived bone marrow cells. Significantly, IACS-10759 extends median survival by over 50 days in an AML orthotopic xenograft model. Furthermore, IACS-10759 also shows selective efficacy in other cell line panels including pancreatic cancer, non-small cell lung cancer and colorectal cancer, and has synergism with glycolysis inhibitors. In light of these results, we are currently performing IND enabling studies for IACS-10759, with first-in-human studies targeted for fourth quarter of 2015.

Citation Format: Marina Protopopova, Madhavi Bandi, Yuting Sun, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Melinda Smith, Jay Theroff, Jing Han, Yuanqing Wu, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. IACS-10759: A novel OXPHOS inhibitor that selectively kills tumors with metabolic vulnerabilities. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A65.
Abstract A72: Novel NAMPT inhibitors for the treatment of Pancreatic cancer
Authors: Chikanna Dinesh , Lakshminarasimhan Anirudha , Khairnar Vinayak , Panigrahi Sunil , Ramanathan Anuradha , Rao Narasimha , Narayanan Kishore , Gopinath Sreevalsam , Ramachandra Raghuveer , Chelur Shekar , Pandit Chetan , Ramachandra Murali
Published: May 2016

Pancreatic cancer is reported to be dependent on NAD salvage pathway for its growth and survival. Nicotinamide phosphoribosyl transferase (NAMPT), an enzyme that catalyzes the rate limiting step of NAD biosynthesis is over expressed in a number of cancers. Inhibition of NAMPT with first generation inhibitors has been demonstrated to result in anti-tumor efficacy in preclinical models. Clinical development of first generation NAMPT inhibitors has been hindered because of their poor pharmacological profile, high cytochrome inhibition and possibly mechanism-based toxicities. Therefore, our objective was to develop NAMPT inhibitors with the “best-in-class” profile with strategies for overcoming mechanism-based toxicities. Utilizing structure-guided drug design including determination of co-crystal structures and SAR-based approaches, we have identified a novel chemical series of inhibitors of NAMPT. Optimization of the series for transient target inhibition as a result of reduced binding strength coupled with desirable pharmacokinetic profile to minimize mechanism based toxicity resulted in identification of AU-4869 as the lead compound. AU-4869 showed potent cross-species activity and reduced strength of binding in comparison with first generation NAMPT inhibitors. Anti-proliferative activity of AU-4869 correlated well with NAD depletion in a pancreatic cancer cell line. The anti-proliferative activities were rescued in NAPRT-proficient cell lines with the addition of nicotinic acid due to the NAMPT independent salvage pathway for biosynthesis of NAD, confirming the mechanism of action through NAD depletion. AU-4869 exhibited desirable drug-like properties including solubility, permeability, metabolic stability, lack of CYP & hERG inhibition and pharmacokinetic exposure upon oral dosing. At well-tolerated doses, AU-4869 exhibited superior efficacy at MTD doses in mice xenograft models as compared to first generation inhibitors. Addition of nicotinic acid improved the tolerability of AU-4869 and reversed the effects of mechanism based toxicity in Rodents. Anti-tumor activities of AU-4869 in the presence of nicotinic acid in NAPRT-deficient pancreatic cancer models are currently being evaluated in preclinical models.

Citation Format: Dinesh Chikanna, Anirudha Lakshminarasimhan, Vinayak Khairnar, Sunil Panigrahi, Anuradha Ramanathan, Narasimha Rao, Kishore Narayanan, Sreevalsam Gopinath, Raghuveer Ramachandra, Shekar Chelur, Chetan Pandit, Murali Ramachandra. Novel NAMPT inhibitors for the treatment of Pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A72.
Abstract B03: Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers
Authors: Wang Zhenghe
Published: May 2016

Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Using isogenic cell lines expressing either wild-type (WT) or oncogenic mutant allele of PIK3CA, we demonstrated that colorectal cancer cells harboring PIK3CA mutations are more dependent on glutamine to grow. In contrast, the isogenic PIK3CA WT and mutant cell lines did not show differential sensitivity to glucose deprivation. Through gene expression analyses, we showed that glutamate pyruvate transaminase 2 (GPT2) is up-regulated in the colorectal cancer cell lines with PIK3CA mutations compared to the isogenic cell lines expressing WT PIK3CA. We demonstrated that induction of GPT2 by mutant p110 alpha is necessary and sufficient to render colorectal cancer cells dependent on glutamine. Moreover, aminooxyacetate, which inhibits enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumor growth of colorectal cancers with PIK3CA mutations, but not colorectal cancers with WT PIK3CA. Thus our data suggest that targeting glutamine metabolism may be an effective approach to treat colorectal cancer patients harboring PIK3CA mutations. Mutant p110 alpha up-regulates GPT2 gene expression through an AKT-independent PDK1-RSK2-ATF4 signaling axis. We showed that ATF4 is a transcription factor that activates GPT2 gene expression. We further demonstrated that mutant p110 alpha activates RSK2 kinase through PDK1. Activated RSK2 then phosphorylates ATF4 at the serine residue 245, which in turn recruits deubiquitinase USP8 and protects ATF4 from ubiquitin-mediated degradation. Lastly, using [13C5-]glutamine isotope-tracing technology, we showed that PIK3CA mutant colorectal cancer cells convert more glutamine to alpha-keto-glutarate to replenish the tricarboxylic acid cycle to generate ATP. Together, our data establish oncogenic PIK3CA mutations as a cause of glutamine addiction in colorectal cancers.

Citation Format: Zhenghe Wang. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B03.
Abstract B29: LRP16 is an essential mediator for DNA double-strand breaks induced NF-kappaB activation
Authors: Wu Zhiqiang , Wang Chunmeng , Bai Miaomiao , Li Xiaolei , Mei Qian , Li Xiang , Wang Yao , Fu Xiaobing , Luo Guangbin , Han Weidong
Published: May 2016

DNA double-strand breaks (DSBs) are an intermediate in several important processes, such as V(D)J recombination, class-switch recombination, and meiosis; and a byproduct of a number of both normal or pathological conditions, such as metabolic respiration and inflammation. Thus, the determination of the proper fates of cells with this specific type of DNA damage, i.e., to repair and survive or to die, constitutes an important element in the homeostasis of individual mammals. The activation of NF-kappaB has emerged as an important mechanism for the modulation of the response to DSBs. The concomitant SUMOylation and phosphorylation of IKKgamma; by the SUMO E3 ligase protein inhibitor of activated STAT (PIASy) and the phosphorylation by ataxia telangiectasia mutated (ATM), respectively, is a key event in this mechanism. However, IKKgamma SUMOylation or phosphorylation can occur separately without activating NF-kappaB. Thus, the mechanism through which mammalian cells are able to accomplish these IKKgamma modifications in a timely and lesion-specific manner remains unclear. In this study, we demonstrate that LRP16 constitutively interacts with PARP1 and IKKgamma. This interaction is essential for efficient interactions among PARP1, IKKgamma, and PIASy, the modifications of IKKgamma, and the activation of NF-kappaB following DSB induction. The regulation of LRP16 in NF-kappaB activation is dependent on its poly (ADP-ribose) binding capability through the unique macro domain. The depletion of the DSB-specific sensor Ku80 resulted in a significant reduction in the physical interactions among LRP16, PARP1 and IKKgamma. Additionally, the knockdown of either endogenous Ku80 or Ku70 by siRNA markedly diminished DSB-induced NF-kappaB reporter gene activity and NF-kappaB target gene expression. These data strongly suggest that LRP16, through its constitutive interactions with PARP1 and IKKgamma, functions to facilitate the lesion-specific recruitment of PARP1 and IKKgamma and, ultimately, the concomitant recruitment of PIASy to IKKgamma in response to DSB damage. Therefore, the study has provided important new mechanistic insights concerning DSB-induced NF-kappaB activation.

Citation Format: Zhiqiang Wu, Chunmeng Wang, Miaomiao Bai, Xiaolei Li, Qian Mei, Xiang Li, Yao Wang, Xiaobing Fu, Guangbin Luo, Weidong Han. LRP16 is an essential mediator for DNA double-strand breaks induced NF-kappaB activation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B29.
Abstract B36: Serum adiponectin levels association with acute leukemias: A meta-analysis
Authors: Dendi Vijaya SenaReddy , Aloor Sivakanth , Keerty Dinesh , Gryn Jeffrey , Gryn Jeffrey
Published: May 2016

Background: Adiponectin, a novel adipokine, secreted by adipocytes in inverse proportion to body fat mass. It is hypothesized that adiponectin exerts a protective role for several type of carcinogenesis, notably those related to obesity including hematological cancers through its anti-apoptotic, anti-inflammatory and anti-angiogenesis properties.

Purpose: The aim of this study is to conduct a meta-analysis to investigate the association between serum adiponectin levels and presence of acute leukemia's.

Methods: We searched MEDLINE, CIINHAL and COCHRANE databases for studies reporting serum adiponectin levels in the peripheral blood with and without acute leukemia's [Acute lymphoblastic leukemia (ALL)/Acute myleogenous leukemia (AML)]. We included case controls, cohort and cross-sectional studies. We calculated the weighted standardized mean difference (SMD) in serum adiponectin levels between the acute leukemia's patients and control groups.

Results: Our search strategy yielded 14 articles and we included 4 studies enrolling 783 participants with 322 patients and 461 controls of matched age, sex and BMI (body mass index). We included 255 ALL patients compared with 240 controls and 67 AML patients compared with 221 controls. The median age of the ALL and AML group compared to controls was 7.39 yrs. (IQR 4.83 – 18.04) and 27 yrs. (IQR 16.03 – 38.08). The median percentage of females of ALL and AML compared to controls was 44.5 (IQR 39.3 – 46.8) and 46.5 (IQR 42.3 – 50.8). The unweighted median serum leptin levels in the ALL and AML groups were 12.65 µg/ml (11.96 – 14.2) and 9.65 µg/ml (6.58 – 12.73) compared to 19.1 µg/ml (17.1 – 20.4) and 27.1 ng/ml (16.03 – 38.08) in the control groups.

The SMD of having abnormal serum adiponectin levels of acute leukemia patients compared to controls was -2.77 (95% CI -4.25 - -1.3) P < 0.001.

Conclusion: Decreased serum adiponectin levels in acute leukemia's i.e. in both ALL and AML are significantly associated with acute leukemia's. Further investigation into the molecular role of serum adiponectin in carcinogenesis is warranted and would perhaps allow for the use of these biomarkers in early diagnosis of acute leukemia.

Citation Format: Vijaya SenaReddy Dendi, Sivakanth Aloor, Dinesh Keerty, Jeffrey Gryn, Jeffrey Gryn. Serum adiponectin levels association with acute leukemias: A meta-analysis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B36.
Abstract B40: AKT-ACLY signaling preferentially maintains histone acetylation over lipid synthesis during nutrient limitation
Authors: Lee Joyce V. , Yuan Zuo-Fei , Liu Shichong , Garcia Benjamin A. , Wellen Kathryn E.
Published: May 2016

Metabolic reprogramming by oncogenes is a mechanism to support biosynthesis and growth in cancer cells. Activation of the PI3K/AKT pathway increases glucose consumption and glycolysis, leading to higher acetyl-CoA production. Extra-mitochondrial acetyl-CoA is utilized in lipid synthesis and protein acetylation. We previously showed that tumor cell histone acetylation is regulated in a glucose-dependent manner, through ATP-citrate-lyase (ACLY) conversion of glucose-derived citrate into acetyl-CoA. In low glucose conditions, acetyl-CoA and histone acetylation levels decrease. However, AKT-dependent phosphorylation of ACLY at serine 455 promotes acetyl-CoA production to allow maintenance of global levels of histone acetylation under glucose limitation. It is unclear whether partitioning of acetyl-CoA between lipid synthesis and histone acetylation in the setting of nutrient limitation impacts cell growth or survival. In this study, we examined whether acetyl-CoA utilization for lipid synthesis is impacted by AKT-ACLY signaling during nutrient limitation. Using 13C-glucose labeling and mass spectrometry, we determined that de novo lipid synthesis is suppressed to a much greater extent than histone acetylation in low glucose conditions. Moreover, phosphorylation of ACLY does not sustain fatty acid synthesis under glucose limitation, in contrast to its effects on histone acetylation. These data indicate that the PI3K-AKT-ACLY axis preferentially maintains histone acetylation over lipid synthesis during nutrient limitation. This regulation is likely due to AMPK-dependent phosphorylation of acetyl-CoA carboxylase (p-ACC), blocking acetyl-CoA commitment to fatty acid synthesis. This study reveals that cancer cells employ robust mechanisms to maintain histone acetylation in nutrient limited environments.

Citation Format: Joyce V. Lee, Zuo-Fei Yuan, Shichong Liu, Benjamin A. Garcia, Kathryn E. Wellen. AKT-ACLY signaling preferentially maintains histone acetylation over lipid synthesis during nutrient limitation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B40.
Abstract B81: Effects of black raspberry diet on the metabolomic profile of C57BL/6J mouse tissues
Authors: Skaer Chad W. , Pan Pan , Young Matthew R. , Wang Hsin Tzu , Oshima Kiyoko , Huang Yi-Wen , Stoner Gary D. , Lechner John , Wang Li-Shu
Published: May 2016

In our previous work, a diet containing 5% freeze-dried black raspberries (BRB) was shown to significantly inhibit colorectal cancer in ApcMin mice. Studies in recent years have shown that metabolomics may help to elucidate the anti-cancer effects of dietary factors. Initially, therefore, we evaluated the effects of black raspberries on the metabolomic profiles of C57BL/6J mice, the mouse strain from which ApcMin mice were derived. In this study, we report the effects of the BRB diet on the metabolomic profiles from C57BL/6J mice. After 8 weeks on a 5% BRB or control AIN-76A diet, feces, liver, and colon mucosa tissues from 9 BRB-fed mice and 7 control-diet fed mice were collected and profiled using mass spectrometry. A total of 424 named metabolites were observed in the liver, feces, and colon mucosa, with 115 metabolites whose levels were significantly different between BRB and control-diet mice (P<0.05). Of these 115 differentiated metabolites, 41 were altered in the colon mucosa, and 38 and 44 metabolites were different in the feces and liver, respectively. Almost all of the changed metabolites in the colon mucosa (36 of 41) were downregulated by the BRB diet, whereas in the feces and liver the majority were upregulated (58 of 82). Included in the upregulated metabolites were lipids and amino acids in the feces and liver tissue. Benzoate derivatives, the product of gut bacteria metabolism of BRB polyphenols, were also up in all tissues. Among the downregulated metabolites were lipids in the colon mucosa and lysolipids in the liver. The decreased levels of lipid metabolites, particularly fatty acids, in the colon mucosa of mice indicates that antagonizing fatty acid synthesis is a potential mechanism by which the BRB diet is altering energy utilization in the colon mucosa of mice.

Citation Format: Chad W. Skaer, Pan Pan, Matthew R. Young, Hsin Tzu Wang, Kiyoko Oshima, Yi-Wen Huang, Gary D. Stoner, John Lechner, Li-Shu Wang. Effects of black raspberry diet on the metabolomic profile of C57BL/6J mouse tissues. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B81.
Abstract IA24: Acetyl-CoA metabolism, gene regulation, and stress management
Authors: Wellen Kathryn E.
Published: May 2016

Acetyl-CoA plays crucial roles at the interface of cellular metabolism, signaling, and epigenetics. This central metabolite is required for de novo biosynthesis of macromolecules such as fatty acids and cholesterol, and it is produced from catabolism of glucose, amino acids, and fatty acids. In addition to its direct metabolic functions, acetyl-CoA serves as the acetyl group donor for both lysine and N-terminal acetylation. Acetyl-CoA availability directly impacts overall histone acetylation levels and participates in gene regulation. In particular, high acetyl-CoA promotes a pro-proliferative gene expression pattern in cancer cells. Diverse signaling and microenvironmental cues impact acetyl-CoA production and utilization, which may influence the ability of cancer cells both to survive in stressful conditions and to grow and proliferate.

In human prostate cancer, both fatty acid synthesis and oxidation have been implicated in tumor growth and proposed as therapeutic targets. Moreover, histone acetylation levels are highly correlated with activation of the PI3K-AKT pathway in human prostate tumors and are predictive of patient outcome. We hypothesized that proper coordination of acetyl-CoA production and utilization is central to the ability of prostate cancer cells to survive and proliferate. In this presentation, I will discuss new data on the role of ATP-citrate lyase in coordinating metabolism, gene expression, and oncogenic signaling to balance stress responses and promote growth and proliferation of prostate cancer cells. The findings point towards novel strategies for therapeutic intervention.

Citation Format: Kathryn E. Wellen. Acetyl-CoA metabolism, gene regulation, and stress management. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA24.
Abstract PR06: Identification of metabolic dependencies in tuberous sclerosis and lymphangioleiomyomatosis
Authors: Filippakis Harilaos , Khabibullin Damir , Priolo Carmen , Henske Elizabeth P.
Published: May 2016

The mammalian target of rapamycin complex (mTORC1) is constitutively active in many human cancers and in Tuberous Sclerosis Complex (TSC). Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease of women in which TSC2-deficient cells metastasize to the lungs, causing cystic lung destruction. LAM can lead to oxygen dependency and death in young women. Inhibition of mTORC1 has a cytostatic effect in LAM and TSC, decreasing the size of kidney and brain tumors and stabilizing lung function. Lifelong therapy appears to be required, since tumors regrow upon treatment cessation.

Hyperactive mTORC1 leads to low autophagic flux, contributing to the metabolic dependencies of TSC-deficient cells. Previously we found that the survival of TSC2-deficient cells is autophagy dependent. A Phase I clinical trial is currently underway testing the combination of rapamycin and hydroxychloroquine (which inhibits autophagy) in LAM. To further define autophagy dependent cellular pathways in TSC2-deficient cells we utilized the L1000 high-throughput gene expression assay. TSC2-null patient-derived cells were treated with chloroquine (CQ, 5 uM) for 24 hrs or 72 hrs. Pathway enrichment analysis revealed that the cholesterol biosynthesis pathway is significantly induced upon CQ treatment. TSC2-deficient cells exhibit differential sensitivity to the combination of CQ and a HMG-CoA reductase inhibitor supporting the L1000 finding.

In parallel, we performed a high throughput synthetic lethality screen of TSC2-deficient and TSC2-expressing cells in the presence or absence of CQ. Four libraries consisting of 4,500 compounds were screened. Six compounds exhibited synergy with CQ by suppressing ATP levels in TSC2-deficient cells but not TSC2-expressing cells. Follow-up analyses of these compounds are ongoing.

In conclusion we utilized gene expression profiling and a high throughput drug screen to identify genetic and chemical perturbations that act synergistically with autophagy inhibition to target TSC2-deficient cells. Abundant data suggests that TSC2-deficient cells can be exploited through their autophagy-dependent metabolic vulnerabilities. Our long-term goal is to identify novel cytocidal therapeutic strategies for clinical translation in TSC and LAM.

Citation Format: Harilaos Filippakis, Damir Khabibullin, Carmen Priolo, Elizabeth P. Henske. Identification of metabolic dependencies in tuberous sclerosis and lymphangioleiomyomatosis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr PR06.
Abstract PR07: Functional identification of a mitochondrial glutamine carrier using isotope tracers
Authors: Metallo Christian
Published: May 2016

Mitochondria are the central metabolic hub of cells, and cells have the ability to metabolize numerous substrates in biochemical pathways within these organelles. Glutamine is a vital nutrient that serves as both nitrogen carrier and anaperotic substrate for mammalian cells. Various cancer cells exhibit dependence on glutaminolysis to fuel bioenergetic and biosynthetic metabolic pathways. This pathway is catalyzed, in part, via mitochondrial glutaminase; however, the mechanism through which glutamine is transported into the matrix is not well known. In fact, the function of nearly half the known mitochondrial solute carriers (SLC25 family) is yet to be described. Using a combination of cell engineering strategies, metabolic tracing using 15N and 13C labeled substrates, and respirometry applied to both intact and permeabilized cultures we have identified a putative mitochondrial glutamine carrier (MQC). Knockdown of this carrier decreases cell growth and drives cells to use alternate pathways for oxidation of glutamine in the TCA cycle. Cancer cells treated with inhibitors of glutaminase exhibit a similar metabolic phenotype as demonstrated via 13C tracing. These results functionally identify a critical node in mitochondrial metabolism and further highlight the utility of metabolic tracing and mass spectrometry for elucidating metabolic function.

Citation Format: Christian Metallo. Functional identification of a mitochondrial glutamine carrier using isotope tracers. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr PR07.
Abstract A28: Osteopontin splicing isoforms expression is modulated by partial epithelial mesenchymal transition in ovarian carcinoma cells.
Authors: Celestino Ingridy , Guimarães Isabella S. , Rangel Leticia B. A. , Gimba Etel R. P.
Published: May 2016

In ovarian carcinoma (OC), invasive cell properties are supported by epithelial mesenchymal transition (EMT). We previously demonstrated that OPNc, one of the glycophosphoprotein osteopontin splicing isoforms (OPN-SI), activates OC progression. However , the involvement of these OPN-SI in EMT in OC cells has not previously been addressed. We aimed to evaluate the expression of OPN-SI in OC cells induced to EMT by TGFβ. ES2 and A2780 OC cell lines were treated with 10ng/ml of TGFβ in order to induce EMT. The expression of OPN-SI and EMT epithelial (E) (Claudin-3, Claudin-4 and E-cadherin) and mesenchymal (M) (slug, vimentin and N-cadherin) markers was tested by quantitative real time PCR. In both cell lines, OPNa is overexpressed in relation to OPNb and OPNc. Upon treatment with TGFβ, in A2780 cells we observed an upregulation of OPNc. Conversely, OPNa and OPNb were downregulated. In ES2 cells, TGFβ also induced OPNc upregulation, but OPNb expression is activated as well, while OPNa expression is inhibited. In order to validate EMT induction by TGFβ, we tested the expression of E and M markers. In A2780 cells, TGFβ induce the downregulation of E-cadherin, but Claudin-3 and Claudin-4 are upregulated. In ES2 cells, Claudin-3 expression is downregulated in this condition. After TGFβ treatment, in A2780 cells all M markers are downregulated, while in ES2 cells, only N-cadherin expression has been inhibited. Our data indicate that the expression of OPN-SI is modulated by EMT induced by TGFβ and that mostly the oncogenic OPNc is upregulated in this condition. Our data evidence that the expression of OPN-SI is modulated by a partial EMT phenotype induced by TGFβ, which is cell-type specific, and that OPN-SI, specially OPNc, could contribute to this key step on tumor progression in OC cells.

Citation Format: Ingridy Celestino, Isabella S. Guimarães, Leticia B. A. Rangel, Etel R. P. Gimba. Osteopontin splicing isoforms expression is modulated by partial epithelial mesenchymal transition in ovarian carcinoma cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A28.
Abstract A34: Activation-induced cytidine deaminase links ovulation-induced inflammation and serous carcinogenesis.
Authors: Sapoznik Stav , Bahar-Shany Keren , Brand Hadar , Pinto Yishay , Gabay Orshay , Glick-Saar Efrat , Dor Chen , Zadok Oranit , Barshack Iris , Zundelevich Adi , Gal-Yam Einav Nili , Yung Yuval , Hourvitz Ariel , Korach Jacob , Beiner Mario , Jacob Jasmine , Levanon Erez Y. , Barak Michal , Aviel-Ronen Sarit , Levanon Keren
Published: May 2016

In recent years, the notion that serous ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway that leads to mutagenesis and genomic instability has not been revealed yet. The mutator enzyme activation-induced cytidine deaminase (AID), which is known to be involved in the process of immunoglobulin somatic hypermutations, has also been recently implicated in inflammation-induced epithelial malignancies. In the current study, we propose that AID is a mechanistic link between ovulation-induced inflammation in FTECs and the genotoxic damage that leads to serous carcinogenesis.

We tested at the expression of AID in human fallopian tube tissues from patients with various gynecological pathologies, as well as in cultured FTECs in an experimental model mimicking normal ovulation. We also looked at the functional effects of AID up regulation in vitro by analyzing double strand DNA breaks, abasic sites, hypomethylation and chromosomal rearrangements. We also performed a comprehensive bioinformatic analysis of somatic mutations patterns in publically available serous carcinoma sequencing data in search of AID mutational fingerprints.

We show that AID, previously shown to be functional only in B lymphocytes, is expressed in human FTECs under physiological conditions, is induced in vitro upon ovulatory-like stimulation and is elevated in vivo under carcinogenesis-associated circumstances. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs.

Overall, our data provides new insights on the etiology of serous ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early-detection.

Citation Format: Stav Sapoznik, Keren Bahar-Shany, Hadar Brand, Yishay Pinto, Orshay Gabay, Efrat Glick-Saar, Chen Dor, Oranit Zadok, Iris Barshack, Adi Zundelevich, Einav Nili Gal-Yam, Yuval Yung, Ariel Hourvitz, Jacob Korach, Mario Beiner, Jasmine Jacob, Erez Y. Levanon, Michal Barak, Sarit Aviel-Ronen, Keren Levanon. Activation-induced cytidine deaminase links ovulation-induced inflammation and serous carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A34.