Abstract B46: The use of quantitative proteomics to increase the knowledge about metabolic symbiosis in a tumor microenvironment
In conclusion, our results illustrate that proteome analysis is a good strategy to obtain insights in the biology of tumor-associated macrophages.Citation Format: Evelyne Maes, Mathias Wenes, Dirk Valkenborg, Inge Mertens, Hans Prenen, Massimiliano Mazzone, Geert Baggerman. The use of quantitative proteomics to increase the knowledge about metabolic symbiosis in a tumor microenvironment. [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 B46. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Maes, E., Wenes, M., Valkenborg, D., Mertens, I., Prenen, H., Mazzone, M., Baggerman, G. Tags: Emerging Analytical Approaches: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B45: Optical spectroscopy of tumor oxygenation and metabolism in preclinical head and neck tumors that fail radiation therapy
The purpose of this study was to determine the role of tumor metabolism and its relationship with tumor oxygenation in driving radiation resistance in head and neck cancer. The use of anatomical endpoints for therapy planning and the evaluation of response to radiation therapy in head and neck squamous cell carcinomas (HNSCC) is problematic because patients who do not respond favorably are losing critical time when alternate interventions could be attempted earlier. The use of a radiolabeled isotope severely limits the frequency of positron emission tomography (PET) of glycolytic demand and therefore the availability of im...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Rajaram, N., Murphy, H. A., Ramanujam, N. Tags: Emerging Analytical Approaches: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B44: Functional identification of a mitochondrial glutamine carrier using isotope tracers
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR07) of the Conference Proceedings.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 B44. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Metallo, C. Tags: Emerging Analytical Approaches: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A44: Expression of metabolic genes is associated with prognosis in breast cancer
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...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Aiderus, A. A. B., Black, M. A., Dunbier, A. K. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B43: The utilization of extracellular proteins as nutrients is suppressed by mTORC1
To engage in growth and proliferation, cells require a continuous supply of precursors for macromolecular synthesis. Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. However, it was recently shown that Ras-induced macropinocytosis of extracellular proteins could reduce a transformed cell's dependence on extracellular amino acids. Here, we show that macropinocytosis and lysosomal catabolism of extracellular proteins can serve as a source of essential amino acids. Lysosomal degradation of internalized proteins can sustain cell survival and induce lysosomal...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Palm, W., Park, Y., Wright, K., Pavlova, N. N., Tuveson, D. A., Thompson, C. B. Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A43: BRAF-mutated melanomas exhibit distinct metabolic programs that may determine therapeutic response
Nearly 60% of melanomas have an activating mutation in the BRAF kinase. Targeted inhibition of mutant BRAF has prolonged overall survival, but responses are highly variable. To investigate the response variability, we utilized a panel of eight BRAF V600E or D mutated melanoma cell lines and treated them with the targeted mutant BRAF inhibitor, PLX4720. Under PLX4720 treatment, the cell lines exhibited a spectrum of concentration-dependent sensitivities based on measured proliferative rates over 96 hours of treatment. Since dysregulated metabolism has been shown to influence therapy resistance, we hypothesized that this spe...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Hardeman, K. N., Peng, C., Paudel, B., Tyson, D., Young, J. D., Quaranta, V., Fessel, J. P. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B42: Metabolic pathway changes induced by a PIK3 mutation and reverted by drugs
In this study we applied two new technologies to elucidate the changes in cellular energy metabolism engendered by a cancer-associated gain-of-function mutation in the PIK3CA gene. We used Phenotype MicroArray Technology to measure and compare the metabolic rates of energy producing pathways in isogenic human breast cells. The isogenic cell lines, were created using new genetic technologies and provided by Horizon Discovery. They included the non-tumorigenic mammary epithelial cell line, MCF10A, which is wild-type for PI3Kα, and two isogenic clonally derived cell lines (CL1 and CL2) in which the endogenous PI3K&alpha...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Lei, X.-H., Noble, S., Bochner, B. R. Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A42: Exploring differential metabolic plasticity for treatment of cancer
The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis even in the presence of sufficient oxygen concentration to perform OXPHOS in mitochondria. In the last years the understanding of cancer metabolism has increased, revealing its high complexity. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, su...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Rodriguez-Colman, M. J., Meerlo, M., Verhoeven-Duif, N., Burgering, B. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B41: Post-transcriptional regulation of IDH1 by the RNA-binding protein HuR is important for pancreatic cancer cell survival under nutrient deprivation
Conclusions: HuR is important for pancreatic cancer cell survival under glutamine deprivation, as previously observed for glucose deprivation. Carbon flux from glutamine to fatty acid end products suggests a role for HuR in reductive carboxylation of glutamine-derived α-ketoglutarate by IDH1, as a way to maintain adequate lipid synthesis under glucose deprivation. Our Studies provide a rationale to pursue pharmacologic strategies that target HuR or its regulation of IDH1 as a novel treatment of PDA.Citation Format: Mahsa Zarei, Fernando F. Blanco, Laszlo G. Boros, Charles J. Yeo, Jonathan R. Brody, Jordan M. Winter. ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Zarei, M., Blanco, F. F., Boros, L. G., Yeo, C. J., Brody, J. R., Winter, J. M. Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A41: Leveraging metabolic dependencies in cancer: Cysteine addiction in pancreatic cancer cells
In conclusion, we find that pancreatic cancer cells are highly sensitive to cysteine-deprivation and to treatment with system xc- inhibitors, and that the cell death caused by this stress is an iron-dependent, oxidative form of cell death called ferroptosis. Furthermore, it appears that GSH, the primary antioxidant molecule of the cell, is not solely responsible for mediating this cell death, arguing that cysteine may play other important roles in maintaining redox homeostasis in these cells. Given that previous studies show that global system xc- knockout mice do not exhibit any changes in cellular GSH content, these find...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Badgley, M. A., Palermo, C. F., Sastra, S. A., Stockwell, B. R., Olive, K. P. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B40: AKT-ACLY signaling preferentially maintains histone acetylation over lipid synthesis during nutrient limitation
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. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Lee, J. V., Yuan, Z.-F., Liu, S., Garcia, B. A., Wellen, K. E. Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B39: PTP1B deficiency potentiate prostate cancer invasiveness by sensitizing Pten-null tumors to high-fat diet
Specific diets can affect the risk and progression of prostate cancer (PCa). However, the interplay between diet and genetic alterations remains ill defined. Here we show that progression of PCa that is driven by Pten loss is mostly unresponsive to a high fat diet; however, in the absence of protein tyrosine phosphatase Ptpn1 (which encodes PTP1B) mice that are fed a high fat diet develop a highly invasive disease that is characterized by increased cell proliferation and Akt activation. Together with the finding that prostate-specific PTP1B overexpression does not initiate PCa by itself, we conclude that PTP1B act as an en...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Labbe, D. P., Uetani, N., Vinette, V., Aubry, I., Migon, E., Sirois, J., Haigh, J. J., Lessard, L., Begin, L. R., Trotman, L. C., Paquet, M., Tremblay, M. L. Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A39: Identification and biostatistical analysis of conserved metabolic profiles in breast tumors from transgenic mouse models
Novel breast biomarkers with prognostic and therapeutic value include metabolites that are differentially expressed in breast tumors. The goal of this study is to identify global metabolic profiles of breast tumors derived from multiple established transgenic mouse models to gain insight into breast cancers of differing origin. We compared breast tumor samples to normal tissue and between cancer models from transgenic mouse breast cancer models overexpressing the following oncogenes: PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg transgenic mice. Our breast tissue samples were analyzed on GC-MS and LC-MS/MS platforms, and analysis i...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Dai, C., Littlepage, L., Li, J. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B38: Melatonin efficacy in breast cancer microenvironment under acidosis
In this study, the benefits of melatonin treatment on cell viability of breast cancer cell lines under acidosis condition were evaluated. Breast cancer cell lines estrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) were cultured in Dulbecco's Modified Eagle's medium (DMEM) at 37°C in 5% CO2. Cell viability was measured using an MTT assay. Individual wells of a 96-well plate were seeded with 100 µL of medium containing 0.05 x 106 cells and cells were separated into the following groups: Group 1) Cells cultured in pH 7.4 with DMEM (control); Group 2) Cells cultured in pH 6.7 with DMEM supplemented ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Sonehara, N. M., Jardim-Perassi, B. V., Mota, A. d. L., Moschetta, M. G., Zuccari, D. A. P. d. C., Paula, R. d. Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B37: Concomitant blockade of glucose uptake and paracrine HGF signaling uncovers the metabolic vulnerability of KRAS-mutant colorectal tumors
Mutations in KRAS and over-expression of MET, the hepatocyte growth factor (HGF) receptor, are both negative prognostic factors for colorectal cancer (CRC). We studied the KRAS-MET interplay using human isogenic CRC cells with defined KRAS status and human HGF knock-in SCID mice, thereby reproducing species-specific HGF-MET paracrine signaling. We show that KRAS-mutant CRC cells display an extraordinary high glycolytic rate that makes them ‘addicted’ to glycolysis. When glucose availability is scarce or upon drug-mediated impairment of glucose metabolism, KRAS-mutant cells rapidly undergo apoptosis, unless &lsq...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Mira, A., Michieli, P. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B36: Serum adiponectin levels association with acute leukemias: A meta-analysis
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 periphera...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Dendi, V. S., Aloor, S., Keerty, D., Gryn, J., Gryn, J. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A36: Amino acids rather than glucose accounts for the majority of cell mass in rapidly proliferating mammalian cells
To facilitate growth and division, proliferating cells must duplicate their mass over the cell cycle. Glucose and glutamine are the most consumed nutrients by proliferating mammalian cells, but the extent to which these and other nutrients contribute directly to cell mass has not been investigated. Using isotope labeled nutrients, we quantified the fraction of cell mass derived from different fuels and find that surprisingly neither glucose nor glutamine provide the majority of carbon present in cells. Instead, amino acids, which are consumed at substantially lower rates, together account for the majority of cell mass. Whi...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Hosios, A. M., Hecht, V. C., Johnson, M., Rathmell, J. C., Manalis, S. R., Heiden, M. G. V. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B35: Association between acute leukemias and levels of leptin in blood: A meta-analysis
Background: Leptin, a secretory protein of adipocytes, shown to induce differentiation, proliferation, anti-apoptotic and activation of hematopoietic cells through paracrine interaction in the bone marrow microenvironment. Existing literature provides conflicting evidence as to the association between levels of serum leptin and acute leukemia's.Purpose: The aim of this study is to conduct a meta-analysis to investigate the association between serum leptin levels and presence of acute leukemia's.Methods: We searched MEDLINE, CIINHAL and COCHRANE databases for studies reporting serum leptin levels in the peripheral blood and...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Dendi, V. S., Aloor, S., Gadde, R., Kunkalla, K., Reddy, R. R. S., Gryn, J. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A35: Cytosolic reductive carboxylation is required for mitochondrial redox homeostasis during anchorage-independent cell growth
Epithelial cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM)1. Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, an essential hallmark of cells capable of metastasis2. Previous study showed that detachment from the ECM is associated with enhanced reactive oxygen species (ROS) levels due to suppression of glucose metabolism in the pentose phosphate pathway3. Here we used metabolic flux analysis to identify an unconventional metabolic pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Jiang, L., Shestov, A., Terada, L. S., Adams, N. D., McCabe, M. T., Pietrak, B., Schimidt, S. J., Schwartz, B., DeBerardinis, R. J. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A34: Impact of a lifestyle intervention on metabolic pathways: Results from the Diet, Exercise, Emotional Processing, and Mindfulness (DEEM) intervention
Background: Breast cancer is the most common non-dermatologic malignancy in women. One-fifth of breast cancers can be attributed to sedentary lifestyles and overweight/obesity. More than two-thirds of U.S. women are overweight or obese. Excess body weight and body fat may affect breast cancer risk through a number of mechanisms, including metabolic pathways (i.e., adipokines, inflammation, and insulin) and estrogen metabolism. To date, limited research has investigated the impact of lifestyle interventions on metabolic changes among women at high risk for breast cancer. The purpose of this pilot study was to test the feasi...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Han, C. J., Korde, L., Reding, S., Reding, K. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B33: Assessing the role of DGAT activity on lipid homeostasis and cancer cell survival
Studies on the effects of modulating the lipid composition of cells have found that increases in saturated fatty acid levels can lead to ER stress, activation of the unfolded protein response (UPR) and cell death. These effects may occur through saturation of the phospholipid pool and subsequent deterioration of ER membrane function. Changes in the composition of the ER membrane can be sensed by the two UPR stress sensors IRE1 and PERK and lead to activation of UPR targets.Rapidly proliferating cancer cells frequently exhibit elevated ER stress due to their increased protein translation rate. In addition, the tumor microen...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Ackerman, D., Qiu, B., Xie, H., Kamphorst, J., Simon, M. C. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A33: CD38 and Nampt regulate tumor cell metabolism through modulation of NAD+
In order to maintain high rates of proliferation, tumor cells must alter their metabolic machinery in favor of increased macromolecule synthesis and energy production. A key factor in tumor cell metabolism is Nicotinamide Adenine Dinucleotide, NAD+. NAD+ is used as a cofactor for catabolic reactions (NAD(H)), or after conversion to NADP(H), for anabolic reactions. In addition, NAD+ is utilized as part of the catalytic mechanism for several classes of enzymes including the sirtuins, PARPs, and CD38. Given the juxtaposition of NAD+ to cell metabolism and other critical cellular process we hypothesize a balance between synthe...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Chmielewski, J. P., Wheeler, F., Cramer, S., Lihong, S., Sirintrapun, J., Kridel, S. J. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B32: FOXOs support the metabolic requirements of normal and tumor cells by regulating IDH1 expression
FOXO transcription factors are considered bona fide tumor suppressors, however recent studies showed FOXOs are also required for tumor survival. Here we identify FOXOs as transcriptional regulators of IDH1. FOXOs regulate IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. In cancer cells carrying mutant IDH1, FOXOs likewise regulate mutant IDH1 expression and maintain the levels of the oncometabolite 2-hydroxyglutarate, which stimulates cancer cell proliferation likely by repressing differentiation. Combined, our data provide a new paradigm for the paradoxical role of FOXOs in bot...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Charitou, P., Rodriguez-Colman, M., Gerrits, J., Verhoeven-Duif, N., Burgering, B. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A32: Structural and molecular mechanisms of human hexokinase 2 in cancer metabolism and apoptosis
Cancer utilizes glucose at elevated levels to support its growth and proliferation, historically known as " Warburg effect". Targeting glucose metabolism in cancer cells to limit its growth will enhance patients' survival rate. Hexokinase catalyzes glucose phosphorylation, and is a major step in regulation of glycolysis. Four isozymes are present in human with Hexokinase 2 (HK2) being the most active and specifically expressed in verity of different cancers. In addition, gene expression profiling experiments of different types of cancer showed high expression levels of HK2, and various biological studies highligh...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Rabeh, W. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B31: Disruption of Folliculin interacting protein-1 modulates Myc-driven metabolism, increasing cell death following metabolic stress
In this study, we examined the potential efficacy of Fnip1 disruption in cancer by disrupting Fnip1 in primary mouse and human B cell lines overexpressing the Myc oncogene. We show that constitutive depletion of Fnip1 in primary pre-B cells, conditional knockdown of Fnip1 in primary mouse mature B cells using the Cre-loxP system, or siRNA-mediated depletion of endogenous FNIP1 from a human B cell line expressing a conditional Myc allele, increase oxidative phosphorylation and Myc-induced glycolysis, which support cell division. Disruption of Fnip1 increases death of primary murine pre-B Eµ-Myc cells and human B cell ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Ramirez, J. A., Tsang, M., Park, H., Margineantu, D., Gu, H., Raftery, D., Hockenbery, D. M., Iritani, B. M. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B29: LRP16 is an essential mediator for DNA double-strand breaks induced NF-kappaB activation
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 markedl...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Wu, Z., Wang, C., Bai, M., Li, X., Mei, Q., Li, X., Wang, Y., Fu, X., Luo, G., Han, W. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A29: Frequency and circadian timing of eating may influence metabolic risk of breast cancer
We examined the associations of eating frequency and timing with metabolic and inflammatory biomarkers putatively associated with breast cancer risk. We used data from a nationally representative sample of adult women participating in the National Health and Nutrition Examination 2009-2010 Survey.Eating frequency and timing variables were calculated from 24-hour food records and included (1) proportion of calories consumed in the evening (between 17.00-00.00h), (2) nighttime fasting duration, and (3) number of eating episodes per day. Multivariable linear regression models examined each eating frequency and timing exposure...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Marinac, C. R., Sears, D. D., Gallo, L. C., Natarajan, L., Breen, C., Patterson, R. E. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A28: Bioenergetic analysis of primary human mammary epithelial cells (hMECs)
We have demonstrated reversible suppression of the tumor suppressor protein p53 by respiratory chain deficiency. Further, a recent study from a different group also suggests genetic inactivation of p53 by the impairments of oxidative metabolism, and mutations in mtDNA and TP53 gene coexist in cancers. Therefore, we predict that variation in oxidative metabolism can result in differences in p53 response among individuals. Conditions that suppress oxidative metabolism can impair p53, and thereby promote cancer development. Toward testing this hypothesis, our approach is to quantify the variation in respiratory activity of no...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Henchey, E. M., Schneider, S. S., Jerry, D. J., Yadava, N. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA27: Exercise, energy balance, and cancer
PhosphoEnol Pyruvate Carboxy Kinase (PEPCK) catalyzes the GTP dependent conversion of oxaloacetate to CO2 and phospo enol pyruvate, which is subsequently converted to glyceraldehyde-3-phosphate, which then serves as precursor for both gluconeogenesis and/or glyceroneogenesis. Using the mouse gene for the cytoplasmic form of PEPCK-Cmus linked to the skeletal muscle actin promoter, PEPCK-Cmus transgenic mice (TG) were engineered on an SJL/B6 background. The PEPCK-Cmus transgenic mice bear 4 allelic copies of PEPCK; they show a nine-fold overexpression of PEPCK in skeletal muscle associated with an increase in muscle glyceron...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Hakimi, P., Feng, Z., Kalhan, S., Berger, N. A. Tags: Systemic Metabolic Alterations and Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract B27: Kras alters expression of asparagine synthetase (Asns) in non-small cell lung cancer (NSCLC) and protects tumors during nutrient stress
Kras is a small GTPase that functions in the transmission of extracellular mitogenic stimuli, and is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC). Previously, Kras has been demonstrated to play a role in tumor metabolism in certain cell types and cancers, but this has yet to be analyzed in the context of NSCLC. We have analyzed how Kras changes metabolic gene expression by expressing a doxycycline-inducible hairpin against Kras in 4 NSCLC cell lines. One of the most regulated metabolism genes is asparagine synthetase (Asns), which transfers the -amino group of glutamine to aspartate, yield...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Gwinn, D. M., Sweet-Cordero, A. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A27: European Network NGS-PTL preliminary data: Whole exome sequencing identifies mutations of ALDH2, RETSAT, HSPG2, CHPF and other metabolic genes as a novel functional category in acute myeloid leukemia
In conclusion, metabolism is the most represented class of mutated genes (8.6% of variants) in our FLT3-WT AML cohort after signaling, leading us to propose a novel functional category. Our data suggest that, along with mutations in established oncogenes and tumor suppressors involved in metabolic control (KRAS, TP53, MYC pathway), a number of genetic determinants participate to leukemia metabolic plasticity and oncogenic mutations of metabolic enzymes may drive leukemogenesis, impact on patient's survival and become novel targets for personalized therapies.Acknowledgements: ELN, AIL, AIRC, progetto Regione-Universit&agrav...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Simonetti, G., Padella, A., Iacobucci, I., Valle, I. D., Fontanarosa, G., Zago, E., Griggio, F., Garonzi, M., Bernardi, S., Papayannidis, C., Abbenante, M. C., Marconi, G., Melloni, G., Riva, L., Guadagnuolo, V., Fontana, M., Bruno, S., Zuffa, E., Franchi Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA26: Identifying metabolic liabilities in obesity-associated pancreatic cancer
Obesity is a rising pandemic that is increasingly being recognized for its striking correlation with the incidence of/mortality from cancers of different tissues, particularly that of the pancreas. Ranking as the fourth leading cause of cancer death in the United States, pancreatic ductal adenocarcinoma (PDAC) is a highly lethal, insidious malignancy whose poor prognosis is reflected in a 5-year survival rate of only 5%. In an obese state characterized by elevated circulating levels of insulin and insulin-like growth factor-1 (IGF-1), metabolic signaling pathways, including PI3K/Akt might be aberrantly regulated, altering ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Zaytouni, T., Dubois, C., Hitchcock, D., Stylopoulos, N., Clish, C., Kalaany, N. Tags: Systemic Metabolic Alterations and Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract IA25: Obesity, metabolism, and cancer: Mechanistic insights from transdisciplinary studies
The prevalence of obesity, an established risk and progression factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Unfortunately, the mechanisms underlying the obesity and cancer connection are poorly understood, and new targets and strategies for offsetting the impact of obesity on cancer risk are urgently needed. We have established in a series of dietary, genetic and pharmacologic studies using genetically-engineered mouse models (GEMMs) of mammary and pancreatic cancer, that insulin and insulin-like growth factor-1 receptor signaling via the Akt/mTOR pathway, as ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Hursting, S. D. Tags: Systemic Metabolic Alterations and Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract B25: Novel hepatic phenotypes caused by conditional c-Myc deletion
The transcription factor c-Myc (hereafter Myc) is among the most frequently deregulated oncoproteins. Inhibition of Myc triggers proliferative arrest of transformed cells and promotes tumor regression and/or apoptosis. Myc is also developmentally necessary and myc-/- embryos die at E9.5-10.5. However, Myc's role in the maintenance of specific tissues has been shown to be of variable importance and necessity. For example, several studies of Myc's role in promoting liver regeneration following partial hepatectomy (PH) have given conflicting results, although all show Myc to be generally dispensable for this function. We have...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Edmunds, L. R., Sharma, L., Otero, P. A., D'Souza, S., Dolezal, J. M., Zeng, X., Ding, Y., Ding, F., Beck, M. E., Kratz, L. E., Vockley, J., Goetzman, E., Scott, D., Yates, N., Duncan, A. W., Prochownik, E. V. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A25: Tumor metabolism as a driver of lethal prostate cancer
Background: Recent evidence suggests that dysregulation of tumor metabolism is a key feature in the progression of normal prostate epithelium to cancer, and that it may also reflect disease aggressiveness and metastatic potential. Identifying and understanding the biologic differences between lethal and non-lethal prostate cancer tumors and illuminating the key mechanisms underlying the progression to a lethal phenotype is critical to the study of this common malignancy.Methods: mRNA was extracted from the tumors of 404 participants of the Health Professionals Follow-up Study and the Physicians' Health Study diagnosed with...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Kelly, R. S., Sinnott, J. A., Rider, J. R., Ebot, E., Gerke, T., Penney, K. L., Bowden, M., Pettersson, A., Loda, M., Stampfer, M., Kantoff, P., Martin, N. E., Giovannucci, E. L., Tyekucheva, S., Heiden, M. V., Mucci, L. A. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA24: Acetyl-CoA metabolism, gene regulation, and stress management
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 ca...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Wellen, K. E. Tags: Metabolic Effects on Epigenetics and Gene Expression: Oral Presentations - Invited Abstracts Source Type: research

Abstract IA23: Use of viruses to study cancer metabolism
Viruses are powerful tools to study cancer metabolism. They trigger major metabolic changes in host cells to meet the bioenergetic and biosynthetic demands of virus infection - changes similar to the enhanced glycolysis and anabolic metabolism widely observed in cancer cells. However, unlike cancer cells, viruses undergo intense selection for efficiency, and rapidly and robustly reprogram host cell metabolism through activation of specific key flux-altering nodes, rather than whole metabolic pathway gene sets. We recently reported that adenovirus infection increases host cell anabolic glucose metabolism via MYC activation ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Christofk, H. R. Tags: Metabolic Effects on Epigenetics and Gene Expression: Oral Presentations - Invited Abstracts Source Type: research

Abstract B23: Mutant NRAS regulates glycolysis in melanoma through ERK, mTOR and the MYC/HIF1{alpha}/MondoA network of transcriptional regulators
Conclusion: NRAS-mutant melanoma cells demonstrate a similar glycolytic phenotype to BRAF-mutant melanoma cells, with MAPK pathway or mTOR inhibition resulting in decreased lactate production, glucose uptake and modulation of the MYC/HIF1α/MondoA network of transcriptional regulators of glycolysis. These findings identify the mechanism of oncogene-driven glycolysis in NRAS-mutant melanoma, and open new possibilities for targeting glycolysis as a therapeutic target in the treatment of patients with NRAS-mutant melanoma.References:1. Parmenter TJ, Kleinschmidt M, Kinross KM et al. Response of BRAF mutant melanoma to BR...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Rao, A. D., Smith, L. K., Parmenter, T. J., McArthur, G. A. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A23: Reversible metabolic changes in human melanoma cells enable distant metastasis
Metastasis is a complex multistep process: cancer cells have to detach from the bulk of the primary tumor, intravasate into the blood, survive anoikis and high shear forces in the blood stream while existing as single cells, extravasate into a distal site, and finally proliferate to form metastatic nodules. Currently our understanding of the mechanisms that govern the metastatic cascade is very limited. Our laboratory has developed a model of melanoma metastasis using patient-derived xenografts in immunocompromised NOD/SCID gamma (NSG) mice. This model is predictive of the clinical outcome in patients: stage III melanomas ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Piskounova, E., Agathocleous, M., Mann, S., DeBerardinis, R., Morrison, S. J. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B22: Acyl-CoA synthetase long-chain family member 3 dependent lipid homeostasis is required for mutant KRAS driven lung cancer
Lung cancer is the leading cause of cancer related deaths in the USA and worldwide. Lung tumorigenesis is a multistep process that involves several genetic aberrations. Activating mutations of the proto-oncogene KRAS (mutant KRAS) occur in ~30% of the cases of human non-small cell lung cancer (NSCLC), which is associated with aggressive, therapy-resistant disease. Despite the recent discovery of low affinity inhibitors, mutant KRAS is a challenging therapeutic target and there is a dearth of therapeutic options for these tumors. Mutant KRAS not only promotes tumorigenesis but also the survival of established lung cancer, b...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Padanad, M. S., Konstantinidou, G., Yang, C., Melegari, M., Venkateswaran, N., Batten, K., Huffman, K. E., Shay, J. W., Minna, J. D., DeBerardinis, R. J., Scaglioni, P. P. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A22: An LKB1-CRTC1 circuit regulates glycosylated COX-2 and predicts drug response in lung cancer
Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins important for mitogenic signaling. Here we report that COX-2 is a transcriptional target of the CREB co-activator CRTC1. In addition, we detected a correlation between the LKB1-null status and presence of 72/74 kDa glycosylated COX-2, but not inactive hypoglycosylated COX-2 in fresh lung adenocarcinoma samples. Since CRTC1 is suppressed by cytoplasmic shuttling following LKB1/AMPK/SIK phosphorylation, we developed an LKB1 signature in lung cancer to search the Connectivity-MAP drug response database. Remarkably, all high-ranking drugs positively associated wi...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Cao, C., Gao, R., Zhang, M., Amelio, A. L., Fallahi, M., Chen, Z., Gu, Y., Hu, C., Welsh, E. A., Engel, B. E., Haura, E., Cress, W. D., Wu, L., Zajac-Kaye, M., Kaye, F. J. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA21: Exploiting metabolic alterations in therapy-induced senescence and drug resistance in a transgenic mouse lymphoma model by reverse and forward omics
Treatment failure is the key determinant of poor outcome in lymphoma therapy. Unveiling the underlying molecular mechanisms is critical to overcome drug insensitivity, may identify novel targets and direct the development of conceptual treatment alternatives. We utilize transgenic mouse lymphoma models as valuable tools for the molecular dissection of treatment responsiveness. Notably, we previously demonstrated the predictive cross-species power of our murine lymphoma model for patients diagnosed with diffuse large B-cell lymphoma (DLBCL) (Reimann-M et al., Cancer Cell, 2010; Jing-H et al., Genes Dev., 2011). Here, we emp...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Schmitt, C. A. Tags: Autophagy and Metabolic Stress in Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract B21: An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation
mTOR senses nutrient and energy status to regulate cell survival and metabolism in response to environmental changes. Surprisingly, targeted mutation of Tsc1, a negative regulator of mTORC1, caused a broad reduction in miRNAs due to Drosha degradation. Conversely, targeted mutation of Raptor, an essential component of mTORC1, increased miRNA biogenesis. mTOR activation increased expression of Mdm2, which is hereby identified as the necessary and sufficient ubiquitin E3 ligase for Drosha. Drosha was induced by nutrient and energy deprivation and conferred resistance to glucose deprivation. Using a high-throughput screen of ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Ye, P., Liu, Y., Chen, C., Tang, F., Wu, Q., Wang, X., Liu, C.-G., Liu, X., Liu, R., Liu, Y., Zheng, P. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A21: ACC1 is required for prostate cancer initiation, but not progression?
The majority of cancers undergo metabolic alterations during initiation and progression of disease. Increased de novo lipogenesis is recognized as metabolic mark of cancer cells. The enzymes responsible for de novo fatty acid synthesis are often overexpressed in cancer, indicating that these enzymes are potential and promising targets for novel therapies. Acetyl CoA Carboxylase 1 (ACC1) is a cytosolic enzyme which catalyzes the rate limiting step of de novo fatty acid synthesis through the ATP and biotin-dependent carboxylation of acetyl-CoA to malonyl-CoA. In doing so, it regulates both fatty acid and acetate metabolism. ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Davis, A. L., Scott, K., Jiansheng, W., Chen, Y. Q., Kridel, S. J. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA20: Hypoxia, metabolism, and tumor progression
The objective is to define the molecular mechanisms by which ARG2 and ASS1 loss alters cellular metabolism to promote ccRCC tumor growth. Delineating these mechanisms will provide new therapeutic avenues to target in this disease.Citation Format: Marie Celeste Simon. Hypoxia, metabolism, and tumor progression. [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 IA20. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Simon, M. C. Tags: Autophagy and Metabolic Stress in Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract A20: Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) regulates metabolic adaptation and enables glucose-independent tumor cell growth
Cancer cells must adapt metabolically to survive and proliferate when nutrients are limiting. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell growth. We found that glucose deprivation stimulated the re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote cell proliferation under low glucose. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine, which was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis....
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Vincent, E. E., Sergushichev, A., Griss, T., Artyomov, M. N., Jones, R. G. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B19: LKB1-AMPK axis regulates the switch of Pyruvate Kinase M isoforms to tolerate nutritional stress
Conclusion: The study highlights the integral role of LKB1-AMPK axis in dynamically regulating the preferential expression of either PKM2 or PKM1 in response to nutritional status in lung cancer and breast cancer cell line models, drawing an inference with regard to real life tumor microenvironment.Citation Format: Gopinath Prakasam, Rameshwar N.K. Bamezai. LKB1-AMPK axis regulates the switch of Pyruvate Kinase M isoforms to tolerate nutritional stress. [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):Ab...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Prakasam, G., Bamezai, R. N. K. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A19: A novel cell line model for chromophobe renal cell carcinoma, UOK276, derived from an aggressive sarcomatoid differentiated tumor
Conclusions: Our study has produced a novel ChRCC cell line model that exhibits a TP53 mutation, commonly seen in ChRCC, and represents a sarcomatoid differentiated region of the tumor. UOK276 should provide a unique in vitro and in vivo preclinical model system for studying the deregulated pathways and testing therapeutic strategies in sarcomatoid differentiated ChRCC.Citation Format: Youfeng Yang, Cathy D. Vocke, Christopher J. Ricketts, Darmood Wei, Hesed M. Padilla-Nash, Shawna L. Boyle, Robert Worrell, Thomas Ried, Maria J. Merino, W. Marston Linehan. A novel cell line model for chromophobe renal cell carcinoma, UOK27...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Yang, Y., Vocke, C. D., Ricketts, C. J., Wei, D., Padilla-Nash, H. M., Boyle, S. L., Worrell, R., Ried, T., Merino, M. J., Linehan, W. M. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B18: Intratumor lysophosphatidylinositol metabolites in a treatment naive patient-derived bone metastatic prostate cancer xenograft
A patient-derived bone metastatic prostate cancer (PCa) xenograft (MDA-PCa-183) was used to investigate early resistance mechanisms after androgen deprivation therapy (ADT). The patient-derived xenograft (PDX) expresses wild-type androgen receptor (AR), TMPRSS2-ERG and was found to have homozygous loss of PTEN [1]. MDA-PCa-183 PDX was established as described by Li et al. [2] using a bone biopsy procured from a patient with metastatic PCa prior to ADT. Tumors were grown in intact male immunodeficient mice (n=23) with a subset of mice (n=16) castrated when they reached a size of approximately 900 mm3. At day 11 after castra...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Titus, M., Araujo, J., Yang, J., Ramachandran, S., Efstathiou, E., Troncoso, P., Logothetis, C., Navone, N. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A18: Changes in cholesterol metabolism support high-density cell growth and therapeutic resistance in glioblastoma multiforme
Glioblastoma Multiforme (GBM) is a highly aggressive, therapeutically resistant brain tumor that arises from cells of astrocytic lineage. The five year survival rate is just below 10% and this statistic has changed very little in the past decade. Amplification and activating mutations of receptor tyrosine kinases (RTKs) are common in GBM; however despite their oncogenic importance, RTK inhibition with tyrosine kinase inhibitors (TKIs) has been clinically ineffective for GBM. The gap between promising laboratory results and clinical success is a common obstacle in cancer research in part because cell culture models do not a...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Kambach, D. M., Kramp, T., Liu, J., Oshinsky, M. L., Bernal, F., Stommel, J. M. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research