Abstract B17: TRIM24 links epigenetics and metabolism in cancer
The TRIpartite Motif (TRIM) family of proteins has approximately 70 proteins, which are involved in a variety of processes, including regulation of protein stability, transcription, cell proliferation and apoptosis. Our laboratory discovered TRIM24, as an E3-ubiquitin ligase of p53, using embryonic stem cells and breast cancer cell lines as model systems. Earlier reports identified TRIM24 as a transcriptional co-regulator of nuclear receptor signaling, directly interacting with retinoic-acid receptor (RAR), thyroid receptor, androgen receptor and estrogen receptor (ER). Since our laboratory's initial report showing TRIM24 ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Thakkar, K. N., Jiang, S., Stratton, S., Barton, M. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A17: Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth
How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1), commonly upregulated in human cancers, is predominantly important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate (a-KG) and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a ROS scavenging enzyme glutathione peroxidase 1 (GPx1) to regulate redox homeostasis, which provides a proliferative advantage to cancer cells and tumor growth. Our findings not on...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Jin, L., Li, D., Alesi, G., Fan, J., Kang, H.-B., Zhou, L., Boggon, T., Jin, P., Egnatchik, R., DeBerardinis, R., Magliocca, K., He, C., Arellano, M., Khoury, H., Shin, D., Khuri, F., Kang, S. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA16: Mapping metabolic drivers of cancer using chemoproteomic and metabolomic platforms
Cancer cells possess fundamentally altered cellular metabolism that not only leads to a re-wiring of cellular biochemistry, but also drives nearly every aspect of cancer cell pathogenicity. While targeting dysregulated metabolism is a promising strategy for cancer treatment, much of cancer metabolism has focused on well-understood metabolic pathways in central carbon metabolism (e.g. glycolytic or glutamine metabolism) underlying cellular transformation and early-stages of cancer, and has largely ignored many of cellular metabolic pathways or those networks involved in cancer progression, despite clear genetic or metabolic...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Nomura, D. Tags: Emerging Analytical Approaches: Oral Presentations - Invited Abstracts Source Type: research

Abstract A16: Restoration of gefitinib sensitivity and upregulation of BIM by simvastatin in T790M mutated non-small cell lung cancer cells
Conclusions: T790M mutation, major mechanism of acquired resistance to EGFR-TKI, was associated with decreased BIM proteins. Simvastatin restored the expression of BIM to induce mitochondrial apoptosis in cells harboring T790M mutation and not in gefitinib sensitive mutation. Our study suggests the possibility of simvastatin to overcome gefitinib resistance with T790M mutation.Citation Format: Mo Jin Young, Lim Jeong Uk, Lee Hwa Young, Kim In Kyoung, Lee Sang Haak. Restoration of gefitinib sensitivity and upregulation of BIM by simvastatin in T790M mutated non-small cell lung cancer cells. [abstract]. In: Proceedings of th...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Young, M. J., Uk, L. J., Young, L. H., Kyoung, K. I., Haak, L. S. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B15: Metastatic breast tumors regulate gene expression at distal mammary sites that predicts patient outcome
This study has future application to our understanding of contralateral breast cancer.Citation Format: Jiyoung Lee, Russell Bainer, Casey Frankenberger, Daniel Rabe, sadiq Saleh, Morag Park, Gary An, Yoav Gilad, Marsha Rich Rosner. Metastatic breast tumors regulate gene expression at distal mammary sites that predicts patient outcome. [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 B15. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Lee, J., Bainer, R., Frankenberger, C., Rabe, D., Saleh, s., Park, M., An, G., Gilad, Y., Rosner, M. R. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B14: Targeting heat shock protein 90 with ganetespib for the treatment of lymphoma
Effective treatments for lymphoma remain a serious unmet medical need: the incidence of lymphoma continues to rise, and lyphoma tumors can relapse in patients who initially respond to treatment. Heat shock protein 90 (HSP90) has become an attractive therapeutic target in treating many cancers including blood cancers. In our study, we show that ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor, dramatically reduced growth of a couple of different kinds of lymphoma, such as mantle cell lymphoma and Burkitt's lymphoma in a dose-dependent manner. It induced G2/M cell-cycle arrest an...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Liu, H., Liang, Z., Zhang, p., Zhao, J., Ruan, L., Lu, Y., Shang, D., Sun, Y., Tu, Z. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A14: Role of mitochondrial folate metabolism in cancer cell growth and proliferation
Conclusions: Mitochondrial folate metabolism is conditionally required for rapid cell growth. High expression of mitochondrial folate genes in cancer may function to meet requirements for one-carbon units, glycine, or redox homeostasis under nutrient stress.Citation Format: Gregory S. Ducker, Mark B. Esposito, Yibin Kang, Joshua D. Rabinowitz. Role of mitochondrial folate metabolism in cancer cell growth and proliferation. [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 A14. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Ducker, G. S., Esposito, M. B., Kang, Y., Rabinowitz, J. D. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA13: The LKB1-AMPK pathway reprograms cancer cell metabolism
The serine/threonine kinase LKB1 is a tumor suppressor gene mutated in the familial cancer condition Peutz-Jeghers syndrome, as well as in 30% of non-small cell lung cancer (NSCLC). One of the critical substrates of LKB1 is AMPK, a highly conserved sensor of cellular energy status that restores metabolic homeostasis following stress. Thus LKB1 is a unique energy-state sensitive regulator of growth and metabolic reprogramming via its effects on AMPK. Our laboratory has performed a three-pronged screen to identify novel substrates of AMPK and related kinases that may mediate LKB1 effects on tumor suppression, metabolism, and...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Shaw, R. J. Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract B13: Akt-independent PDK1 signaling in regulation of purine biosynthesis
Molecular association of cancer cell metastasis with signaling pathways has been explicated so as to aid in the development of new prognostic models for better cancer therapies. However, those metastatic signaling pathways are barely explored to take account of the functions of enzymes involved in cellular metabolism. Particularly, the metabolic enzymes in de novo purine biosynthesis have been overlooked for their potential roles in cancer cell metastasis even though they have been successfully validated anti-cancer drug targets. Meanwhile, several lines of recent discoveries on de novo purine biosynthesis suggest that the...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: An, S. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR12: Transcriptional regulation of metabolism by MLX and its binding partners is essential for tumor cell survival and spermatogenesis
Conclusions: Transcriptional coordination between the mitogen- and nutrient-responsive arms of the MAX/MLX network exhibits context-dependent lethality. MondoA and Chrebp exhibit non-redundant functions in both cancer cells and normal mouse tissue, and inactivation of Mlx phenocopies loss of both factors, suggesting that targeting Mlx can inhibit both MondoA and Chrebp transcriptional activity and subsequent metabolic output. Metabolic regulation by Mlx impacts normal testicular tissue homeostasis and differentiation in the mouse, and its deregulation is associated with human diseases such as loss of function associated wi...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Carroll, P. A., Diolaiti, D., Cheng, P.-F., Gu, H., Djukovic, D., Raftery, D., Ayer, D. E., Muller, C. H., Eisenman, R. N. Tags: Cancer Metabolic Pathways: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B12: Yes-Associated Protein: A master metabolic regulator In medulloblastoma
Downstream of mitogenic Sonic hedgehog (Shh) signaling, Yes-Associated Protein (YAP) can drive proliferation in Cerebellar Granule Neural Progenitor (CGNP) cells. CGNPs are the proposed cells of origin of SHH medulloblastomas. They are a neural progenitor type whose developmental expansion requires signaling by Shh, a secreted ligand produced by the neighboring Purkinje neurons. Approximately 30% of human medulloblastomas bear an activated Sonic hedgehog pathway gene expression signature. Ectopic expression of YAP promotes highly aggressive Shh-driven medulloblastoma growth and radio-resistance (Fernandez et al., 2009). Me...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Malhotra, A., Dey, A., Kenney, A. M. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A12: Establishment of myeloid lineage cell line that resembles myeloid-derived suppressive cells
Myeloid-derived suppressive cells (MDSCs) are inflammatory cells that play critical roles in promoting cancer growth and metastasis. In order to facilitate characterization of biochemical and cellular mechanisms of MDSCs, it is urgent to establish an "MDSC-like" cell line for pharmacological and immunotherapeutic applications. Lysosomal acid lipase (LAL) is a critical lipid enzyme in the metabolic signaling pathway that hydrolyzes cholesteryl esters (CE) and triglycerides (TG) in lysosomes. In mice, lack of LAL in genetically ablated knockout mice (lal-/-) shows systemic expansion of MDSCs, which directly stimula...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Yan, C., Ding, X., Wu, L., Du, H. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR11: Tissue-of-origin dictates the metabolic fate of branched chain amino acids in mutant Kras-driven cancers
Conclusions: Despite sharing an identical combination of mutations, mouse models of NSCLC and PDAC exhibit distinct phenotypes with regards to BCAA metabolism in tumors. The different fates of BCAAs in each of these tumor types might explain previously observed alterations in plasma BCAA levels and provides further insight into how tumors can influence whole body metabolic phenotypes in early cancer.1. Hu, J., et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nature biotechnology 31, 522-529 (2013).2. Yuneva, M.O., et al. The Metabolic Profile of Tumors Depends on Both the Respon...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Mayers, J. R., Torrence, M. E., Davidson, S. M., Papagiannakopoulos, T., Lau, A. N., Jacks, T., Heiden, M. G. V. Tags: Systemic Metabolic Alterations and Cancer: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA11: Systematic approaches to understanding cellular metabolism
mTOR is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth and proliferation. We now appreciate that this pathway becomes deregulated in many human cancers and has an important role in the control of metabolism and aging. We have identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival through Akt. These complexes, mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. I will discuss new res...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Sabatini, D. M. Tags: Signaling Pathways and Cancer Metabolism: Oral Presentations - Invited Abstracts Source Type: research

Abstract A11: Myeloid-derived suppressor cells suppress immune surveillance and stimulate cancer cell proliferation/metastasis through activation of mTOR pathway in lal-/- mice
Inflammation critically contributes to cancer metastasis, in which myeloid-derived suppressor cells (MDSCs) are an important participant. Although MDSCs are known to suppress immune surveillance, their roles in directly stimulating cancer cell proliferation and metastasis currently remain unclear. MDSCs development and homeostasis is controlled by lysosomal acid lipase (LAL), a critical enzyme in the metabolic signaling pathway that hydrolyzes cholesteryl esters (CE) and triglycerides (TG) in lysosomes. Lysosomal acid lipase (LAL) deficiency causes systemic expansion and infiltration of MDSCs in multiple organs. LAL-defici...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Du, H., Zhao, T., Ding, X., Walls, K., Yan, C. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR10: Serine biosynthesis from glucose regulates folate availability
It has been established that de novo serine biosynthesis is important for some cancers. We have previously shown that phosphoglycerate dehydrogenase (PHGDH), the enzyme responsible for catalyzing the first step in glycolytic serine biosynthesis, is amplified in certain cancers, including breast cancer and melanoma. Knockdown of PHGDH results in decreased proliferation of PHGDH-amplified cells, demonstrating a dependence on PHDGH in these cells; however, it has not been possible to rescue this defect with exogenous serine, suggesting that glycolytic serine biosynthesis has an alternate function in cells. Here we have invest...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Lewis, C. A., Fiske, B. P., Pacold, M. E., Hosios, A. M., Mattaini, K. R., Sabatini, D. M., Heiden, M. G. V. Tags: Cancer Metabolic Pathways: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B10: Noninvasive pharmacodynamic markers of the dual mTORC1/2 inhibitor AZD2014 in combination with paclitaxel, in cisplatin-resistant ovarian carcinoma xenografts
Background: The PI3K/AKT/mTOR pathway is known to regulate glucose metabolism, proliferation and apoptosis, hence the inhibition of mTOR is expected have impact on these important mechanisms of tumor growth and survival. Studies of cancer metabolism following mTOR inhibition reported to date have only been carried out on allosteric mTOR inhibitors which selectively inhibit the activity of mTORC1. The metabolic changes associated with dual mTORC1 and 2 inhibitions remain unknown. AZD2014 is a dual mTORC1/2 inhibitor. The aims of this study are to (i) examine the effects on tumor metabolism following mTORC1/2 inhibition alon...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Te-Fong, A.-C. L. W., Papaevangelou, E., Leach, M. O., Banerji, U., Chung, Y.-L. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A10: SLC7A11 contributes to the pathogenesis of lung cancer
Introduction: Many tumors increase uptake and dependence on nutrients such as glucose, cysteine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer. Here, we investigated the function of SLC7A11 (xCT), a cystine/glutamate anti-porter, in the pathogenesis of lung cancer. Recently, we found xCT to be strongly overexpressed at the cell surface of lung cancers and began to investigate the mechanisms by which xCT may contribute to lung cancer progression.Methods: The expression of xCT and its related genes in 411 patients with non small cell lung...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Ji, X. J., Qian, J., Rahman, J., Harris, B., Hoeksema, M., Chen, H., Eisenberg, R., Young, J. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B09: Mitochondrial respiration controlled by survivin directs mitochondrial dynamics and tumor cell invasion
In this study, with the use of sirRNA and pharmacological approaches against survivin, as well as protein reconstitution experiments, we dissect the role of mitochondrial survivin in modulating tumor bioenergetics. Biochemically, this study identifies mitochondrial survivin as part of a multi-protein complex with mitochondrial chaperone TRAP-1 and oxidative phosphorylation Complex II subunits. Survivin recruitment to this complex ensures protein folding and oxidative phosphorylation activity. Interference with this pathway inhibits cellular respiration, ATP production and induces cellular starvation. Functionally, this mul...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Rivadeneira, D. B., Caino, M. C., Seo, J. H., Angelin, A., Douglas, W. C., Languino, L. R., Altieri, D. C. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A09: The role of asparagine in glutamine-independent proliferation of breast cancer cells
In this study, we attempt to elucidate the mechanism by which asparagine facilitates the biomass accumulation and proliferation of glutamine-independent cell types. First, we investigate whether luminal breast cancer cells may possess an ability to catabolize asparagine in a manner similar to glutaminolysis and thus use it as an alternative source of reduced nitrogen and carbon in a setting of glutamine deprivation. Second, we explore a potential regulatory metabolic function of asparagine, whereby it may regulate cellular glutamine synthesis and thus enable proliferation in conditions of glutamine deprivation.Citation For...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Pavlova, N. N., Thompson, C. B. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B08: Metabolic adaption in inflammatory macrophages through the modulation of Fe-S cluster biogenesis factors
Macrophages are among the most abundant normal cells in the tumor microenvironment, and the mechanistic overlap in the metabolic changes in glycolytic cancer cells and inflammatory immune cells suggest that insights into the mechanisms underlying the metabolic changes could be useful in the treatment of both cancers and inflammatory diseases. Metabolic choices in immune cells are tightly linked to cell fate and function. Inflammatory immune cells, such as M1 macrophages and T-helper 17 cells, undergo a shift from OXPHOS to enhanced glucose uptake, glycolysis and the pentose phosphate pathway, whereas anti-inflammatory cell...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Tong, W.-H., Maio, N., Rouault, T. A. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A08: The role of branched-chain amino acid metabolism in Myc-driven malignancies
Cancer cells have high metabolic demands. Myc oncoproteins function as transcription factors and are overexpressed in a number of human malignancies. Myc induces the transcription of a number of genes involved in glycolysis and glutaminolysis, including those encoding transporters of glucose, glutamine, lactate and branched-chain amino acids (BCAA: valine, leucine and isoleucine, via LAT1/SLC7A5). Tumors driven by Myc are dependent on and utilize L-glutamine to feed carbon intermediates into the Krebs Cycle. We reasoned that Myc would also control the catabolism of BCAA, which also provides key metabolic intermediates, spe...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Fernandez, M. R., Damoulis, V. A., Wang, W., Radlwimmer, B., Cleveland, J. L. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR07: Functional identification of a mitochondrial glutamine carrier using isotope tracers
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 carrie...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Metallo, C. Tags: Emerging Analytical Approaches: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA07: Exploiting cancer metabolism for cancer therapy
I will describe two approaches for cancer therapy, which exploit distinct intracellular metabolism in cancer cells to selectively eradicate them. In the first part of my presentation I will describe how we could target hexokinase 2 for cancer therapy, and without any overt physiological consequences. In the second part of the presentation I will describe how we could exploit high levels of reactive oxygen species (ROS) in cancer cells displaying hyperactive Akt to selectively eradicate these cancer cells and to evade chemoresistance induced by hyperactivation of Akt.Hexokinases, which catalyze the first committed step in g...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Hay, N. Tags: Therapeutic Targets From Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract A07: Inhibiting radiation-induced reprogramming of breast cancer cells via metabolic perturbation
Conclusions: Radiation-induced dedifferenatiation of nonstem breast cancer cells into BCSCs has major implications for treatment of breast cancer in the clinic. In order to achieve long-lasting tumor control in breast cancer, eliminating the intrinsic BCSCs will not be sufficient, as recent evidence demonstrates that radiation therapy can dedifferentiate surviving breast cancer cells into BCSCs, which have the ability to re-initiate breast tumor. Here, we demonstrate that the process of dedifferentiation during radiation therapy has specific metabolic requirements. Interfering with these requirements can greatly impair the...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Dratver, M. B., Siu, R. T., Boyer, S., Nguyen, A., Frohnen, P., Pajonk, F., Vlashi, E. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR06: Identification of metabolic dependencies in tuberous sclerosis and lymphangioleiomyomatosis
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 lymphangioleio...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Filippakis, H., Khabibullin, D., Priolo, C., Henske, E. P. Tags: Autophagy and Metabolic Stress in Cancer: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA06: De novo purine biosynthesis dictates glutamine dependency of glioblastoma cells
L-Glutamine has the unique physiological function of balancing carbon and nitrogen requirements of tissues. It has been proposed that cancer cells undergoing aerobic glycolysis require glutamine carbons to replenish the tricarboxylic acid (TCA) cycle and sustain accelerated anabolism (anaplerosis). Yet we showed that, in glioblastoma (GBM) cells, about half of the glutamine-derived glutamate is secreted out of the cells and does not enter the TCA cycle. In the absence of glutamine, replenishment of the TCA cycle is insufficient to restore cell proliferation. In contrast, cataplerotic reactions culminating with the conversi...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Gottlieb, E. Tags: Therapeutic Targets From Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract B06: TSC2 loss induces aberrant choline lysoglycerophospholipid metabolism
Tuberous Sclerosis Complex (TSC) is an autosomal dominant disease characterized by multi-organ proliferation of TSC2-deficient cells with aberrant activation of the mechanistic/mammalian Target of Rapamycin Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Up to 80% of women with TSC develop lymphangioleiomyomatosis (LAM), which consists of diffuse proliferation of TSC2-deficient smooth muscle-like cells with progressive cystic destruction of the lung. LAM can also occur as a sporadic disorder of women. A downstream effector of mTORC1, the Sterol Regulatory Element-Binding Protein (SREBP), regulates the...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Priolo, C., Ricoult, S. J. H., Khabibullin, D., Filippakis, H., Yu, J., Manning, B., Clish, C., Henske, E. P. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR05: Aspartate metabolism links the urea cycle with nucleic acid synthesis in cancerous proliferation
Argininosuccinate synthase (ASS1) is a urea cycle cytosolic enzyme that conjugates aspartate transported across the mitochondria and citrulline. In the liver, this is a critical step in conversion of nitrogenous waste to urea, whereas in most other tissues, it is the penultimate step in arginine synthesis. Citrullinemia is a urea cycle disorder caused by germline mutations that lead to decreased flux through ASS1. Citrullinemia type I (CTLN I) is caused by ASS1 deficiency and citrullinemia type II (CTLN II) is caused by deficiency in mitochondrial aspartate transporter Citrin. In contrast to the established role of ASS1 in...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Rabinovich, S., Yizhak, K., Sun, Q., Brandis, A., Helbling, D., Dimmock, D., Nagamani, S., Ruppin, E., Erez, A. Tags: Cancer Metabolic Pathways: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B05: Inhibition of ER/Stat3 signaling pathways drive the evolution of ER+ metastatic breast cancer through the generation of ER-independent OXPHOShi self-renewing cells
A better understanding of the molecular features of the metastatic switch might reveal new cancer cell liabilities to develop novel therapeutics for metastatic cancer patients. Here we demonstrated that the generation of dormant and tumor-initiating cells takes place in the tumor microenvironment through a metabolic reprogramming in luminal (ER+) breast cancer. The expression of the surface markers interleukin 6 receptor (IL6R) and CD44 identify distinct tumor initiating and dormant cells. We demonstrated that IL6Rlo/CD44hi cells originate in hypoxic niches and self-renew following re-oxygenation via estrogen receptor alph...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Sansone, P., Berishaj, M., Chang, Q., Strillacci, A., Giacco, F., Bromberg, J. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR04: HIF-2{alpha} dependent lipid storage promotes endoplasmic reticulum homeostasis in clear cell renal cell carcinoma
Clear cell renal cell carcinoma (ccRCC) is the most common form of renal cancer, defined pathologically by abundant intracellular lipid droplets (LDs) that impart the clear cell phenotype, and molecularly by constitutive activation of the hypoxia inducible factors (HIFs). The primary aim of this study was to identify the mechanisms driving enhanced neutral lipid storage and the function of this phenotype in ccRCC. Our work demonstrates that HIF-2α promotes neutral lipid storage in ccRCC through up-regulation of the LD coat protein PLIN2. Expression profiling in multiple cohorts of primary ccRCC and normal kidney samp...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Qiu, B., Ackerman, D., Sanchez, D. J., Li, B., Ochocki, J. D., Grazioli, A., Bobrovnikova-Marjon, E., Diehl, J. A., Keith, B., Simon, M. C. Tags: Autophagy and Metabolic Stress in Cancer: Oral Presentations - Proffered Abstracts Source Type: research

Abstract A04: Differential dependence on sphingolipid metabolism in the normal and leukemic human hematopoietic hierarchy
Metabolic alterations are a cancer hallmark that are typically evaluated in bulk tissues. However most normal tissues and cancers are hierarchically organized and the metabolic requirements of both normal and cancer stem cells are poorly understood, particularly beyond energy metabolism. By analyzing a comprehensive transcriptional roadmap of human hematopoiesis, and comparing this to a leukemia stem cell (LSC) signature developed from 84 human acute myeloid leukemia (AML) samples, we found that: (1) several metabolic pathways, specifically in bioactive lipids, distinguish normal hematopoietic stem cells (HSC) from progeni...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Xie, S. Z., Laurenti, E., Ferrari, R., Dick, J. E. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR03: P53 inhibits the expression of the pyrimidine catabolic gene Dihydropyrimidine dehydrogenase (DPYD)
Fluorouracil (5-FU) a widely used chemotherapeutic drug whose unpredictable pharmacokinetics is controlled by the pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD), that has recently also been shown to be a gatekeeper of the epithelial-to-mesenchymal transition (EMT) in breast cancer. Relatively little is known about the transcriptional control of DPYD and here we show for the first time an interaction between p53 and DPYD (involved in catabolism of pyrimidines as well as 5-FU) where p53 represses both the base-line expression of DPYD and that following 5-FU administration in vitro and in vivo. This mechanis...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Gokare, P. R., Finnberg, N., Dai, J., El-Deiry, W. Tags: Cancer Metabolic Pathways: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA03: Metabolic heterogeneity in cancer cells and tumors
Most diseases are accompanied by altered metabolism at the cellular level. In cancer, metabolic reprogramming that is, the regulated alteration of metabolism as a consequence of tumorigenic mutations and other factors is viewed as an essential component of malignant transformation. Research in cancer metabolism is motivated in part by the hope that understanding the basis of metabolic reprogramming will stimulate the development of new approaches in cancer imaging and therapy, both of which have historically capitalized on the altered metabolic states of tumors. Over the past decade, a large number of mechanisms by which o...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: DeBerardinis, R. J. Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Oral Presentations - Invited Abstracts Source Type: research

Abstract B03: Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers
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 iso...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Wang, Z. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A03: Procyanidin B2 3,3"-di-O-gallate from grape seed causes metabolic alterations in prostate cancer cells: 1H-, 13C- and 31P-NMRS-based metabolomics study
We examined global metabolic profile, including glucose metabolism, energy state, and lipid metabolism in these cells after B2G2 treatment. The time-course of B2G2 effects on glucose uptake and lactate release was also studied in the media of B2G2-treated PCa cells from 4-72 hrs of treatment. Results indicated that there was differential effect of B2G2 on mitochondrial glucose metabolism in these cells. While glucose uptake was markedly reduced as a function of time, there was also a significant decrease in extracellular lactate export with increased B2G2 exposure-time. Importantly, B2G2 preserved citrate concentration in ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Raina, K., Kumar, D., Agarwal, R., Agarwal, C. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B02: mTOR/S6K pathway-dependent metabolic reprogramming in cancer cells mediates resistance to glycolytic inhibitors
The targeting of "glycolytic addiction" in cancer has been an attractive proposition since the time the Warburg effect was reported in the 1940s. However this has not been successful in the clinic thus far, as the outcome of numerous clinical trials with glycolytic inhibitors has not been encouraging either due to minimal efficacy at lower tolerable doses or undue toxicity at higher effective doses. We hypothesized that the extensive cross-talk between the glycolytic pathway and other networks of cellular metabolism offers prospective avenues through which cancer cells can escape inhibition of any one node in the...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Pusapati, R., Gao, M., Daemen, A., Hatzivassiliou, G., Settleman, J. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A02: OXPHOS inhibition and pentose phosphate pathway induction are early events priming preneoplastic lesions toward HCC development
Conclusion: Our results demonstrate that Warburg metabolic deregulation and PPP induction are early events in HCC development. Crucially, TRAP1 and NRF2 are key regulators of this metabolic reprogramming in preneoplastic hepatocytesCitation Format: Marta A. Kowalik, Giulia Guzzo, Andrea Morandi, Andrea Perra, Silvia Menegon, Maria M. Angioni, Silvia Giordano, Paola Chiarugi, Andrea Rasola, Amedeo Columbano. OXPHOS inhibition and pentose phosphate pathway induction are early events priming preneoplastic lesions toward HCC development. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-1...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Kowalik, M. A., Guzzo, G., Morandi, A., Perra, A., Menegon, S., Angioni, M. M., Giordano, S., Chiarugi, P., Rasola, A., Columbano, A. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR01: Role of mitochondrial folate transporter in metabolism of tumor cells
The objective of the present study is to identify modulators of cellular metabolism among transportome genes which could potentially be exploited as targets in pancreatic ductal adenocarcinoma (PDAC). Indeed cancer cells have the ability to adapt in order to survive stressful environment where oxygen and nutrients are limited due to the poor vasculature and outgrowth of stromal component. Thus, disrupting mechanisms of metabolic adaptation could inhibit tumor proliferation or sensitize tumor cells to treatment. Ion channels and transporters provide the link between cancer cells, stroma and matrix. Additionally these protei...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Kovalenko, I., Schockel, L., Glasauer, A., Haegebarth, A., Christian, S. Tags: Therapeutic Targets From Cancer: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B01: Multilevel interference with receptor-PI3K-mTORC1 signaling is key mechanism for anticancer activity of fatty acid synthase inhibitors
The metabolic oncogene fatty acid synthase (FASN) is overexpressed in 80% of ovarian cancers (OC) and indicates poor prognosis. Exposure of OC to inhibitors of FASN elicits a complex stress response that interferes with receptor-PI3K-mTORC1 signaling (briefly designated ‘PI3K pathway’). Here we demonstrate that FASN inhibitors capitalize on multiple mechanisms to interfere with the PI3K pathway, and that silencing this cascade is crucial for the anticancer action of the drugs. Data were obtained using thin-layer chromatography, ELISA, Western blotting, quantitative micropatterning and growth assays, respectivel...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Wagner, R., Prostling, K., Veigel, D., Stubiger, G., Grusch, M., Weghuber, J., Singer, C., Karlic, H., Colomer, R., Benhamu, B., Lopez-Rodriguez, M. L., Hegardt, F., Garcia, J., Serra, D., Valent, P., Grunt, T. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A01: ADRB2 regulates phase II steroid metabolism and determines development of castration-resistant prostate cancer
The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) are not fully understood. The β2-adrenergic receptor (ADRB2) is a key regulator of a wide range of metabolic processes in the body, and it has been implicated in androgen receptor signaling and development of CRPC. We have unpublished data which shows that low expression of ADRB2 predicts a more rapid development of CRPC. Based on this finding, we wanted to investigate whether the ADRB2 level/activity impacts cellular features to help explain how and why the receptor has prognostic value in prostate cancer.We stabl...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Braadland, P. R., Grytli, H. H., Ramberg, H., Katz, B., Gauthier-Landry, L., Kellmann, R., Krobert, K. A., Wang, W., Svindland, A., Levy, F. O., Berge, V., Mellgren, G., Barbier, O., Tasken, K. A. Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research

Mitogenic Hedgehog Signaling and Mitochondria Form
This report uncovers a surprising decrease in mitochondrial membrane potential (MMP) and overall ATP production in CGNPs exposed to Shh, consistent with increased glycolysis resulting in high intracellular acidity, leading to mitochondrial fragmentation. Ultrastructural examination of mitochondria revealed a spherical shape in Shh-treated cells, in contrast to the elongated appearance in vehicle-treated postmitotic cells. Expression of mitofusin 1 and 2 was reduced in these cells, although their ectopic expression restored the MMP to the nonproliferating state and the morphology to a fused, interconnected state. Mouse Shh ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Malhotra, A., Dey, A., Prasad, N., Kenney, A. M. Tags: Signal Transduction Source Type: research

Periostin-ITGB3 Signaling Maintains Breast CSCs
Basal-like breast cancer (BLBC) is an aggressive subtype of breast cancer which is often enriched with cancer stem cells (CSC), but the underlying molecular basis for this connection remains elusive. We hypothesized that BLBC cells are able to establish a niche permissive to the maintenance of CSCs and found that tumor cell-derived periostin (POSTN), a component of the extracellular matrix, as well as a corresponding cognate receptor, integrin αvβ3, are highly expressed in a subset of BLBC cell lines as well as in CSC-enriched populations. Furthermore, we demonstrated that an intact periostin–integrin &bet...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Lambert, A. W., Wong, C. K., Ozturk, S., Papageorgis, P., Raghunathan, R., Alekseyev, Y., Gower, A. C., Reinhard, B. M., Abdolmaleky, H. M., Thiagalingam, S. Tags: Signal Transduction Source Type: research

CBM Complex in Breast Cancer
The HER2/Neu protein is overexpressed in a large fraction of human breast cancers. NF-B is one of several transcription factors that are aberrantly activated in HER2-positive breast cancers; however, the molecular mechanism by which HER2 activates NF-B remains unclear. The CARMA3–BCL10–MALT1 (CBM) complex is required for GPCR- and EGFR-induced NF-B activation. In the current study, the role of the CBM complex in HER2-mediated NF-B activation and HER2-positive breast cancer was investigated. Interestingly, HER2-mediated NF-B activation requires protein kinase C (PKC) activity rather than AKT activity. Using bioc...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Pan, D., Zhu, Y., Zhou, Z., Wang, T., You, H., Jiang, C., Lin, X. Tags: Signal Transduction Source Type: research

Beige/Brown Adipose Markers and Breast Cancer
In this study, we demonstrate enrichment of beige/brown adipose markers, contributed from the host as well as tumor cells, in the xenografts from breast cancer cell lines. In addition to uncoupling protein-1 (UCP1) that is exclusively expressed in beige/brown adipocytes, gene expression for classical brown (MYF5, EVA1, and OPLAH) as well as beige (CD137/TNFRSF9 and TBX1) adipocyte markers was also elevated in the xenografts. Enrichment of beige/brown characteristics in the xenografts was independent of the site of implantation of the breast tumor cells. Early stages of xenografts showed an expansion of a subset of mammary ...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Singh, R., Parveen, M., Basgen, J. M., Fazel, S., Meshesha, M. F., Thames, E. C., Moore, B., Martinez, L., Howard, C. B., Vergnes, L., Reue, K., Pervin, S. Tags: Oncogenes and Tumor Suppressors Source Type: research

p53 Mutation/Loss Enhances mTORC1 Activity
This study establishes that loss of p53 function decreases lysosomal TSC2 and increases lysosomal Rheb resulting in hyperactive mTORC1, findings that are consistent with a more malignant phenotype. Mol Cancer Res; 14(1); 66–77. ©2015 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Agarwal, S., Bell, C. M., Taylor, S. M., Moran, R. G. Tags: Oncogenes and Tumor Suppressors Source Type: research

p53 Activity Dominates That of p73 Caused by Mdm4 Loss
In this study, the significance of the Mdm4 and p73 interaction in vivo during embryogenesis and tumorigenesis was examined. The data revealed that p73 loss did not rescue either the early Mdm4-deficient embryonic lethality or the runted phenotype of Mdm42/2 p53+/– embryos. Furthermore, studies in the developing central nervous system wherein both genes have prominent roles indicated that loss of p73 also did not rescue the Mdm4-null brain phenotype as did p53 loss. This p53 dependency occurred despite evidence for p73-specific transcriptional activity. In tumor studies, the combination of Mdm4 overexpression and p73...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Tashakori, M., Zhang, Y., Xiong, S., You, M. J., Lozano, G. Tags: Oncogenes and Tumor Suppressors Source Type: research

BRCA2 and RAD51 Promote Oncolytic Adenovirus Activity
Homologous recombination (HR) function is critically important in high-grade serous ovarian cancer (HGSOC). HGSOC with intact HR has a worse prognosis and is less likely to respond to platinum chemotherapy and PARP inhibitors. Oncolytic adenovirus, a novel therapy for human malignancies, stimulates a potent DNA damage response that influences overall antitumor activity. Here, the importance of HR was investigated by determining the efficacy of adenovirus type 5 (Ad5) vectors in ovarian cancer. Using matched BRCA2-mutant and wild-type HGSOC cells, it was demonstrated that intact HR function promotes viral DNA replication an...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Tookman, L. A., Browne, A. K., Connell, C. M., Bridge, G., Ingemarsdotter, C. K., Dowson, S., Shibata, A., Lockley, M., Martin, S. A., McNeish, I. A. Tags: DNA Damage and Repair Source Type: research

HDAC Inhibition for the Treatment of Epithelioid Sarcoma
Epithelioid sarcoma is a rare neoplasm uniquely comprised of cells exhibiting both mesenchymal and epithelial features. Having propensity for local and distant recurrence, it poses a diagnostic dilemma secondary to pathologic complexity. Patients have dismal prognosis due to lack of effective therapy. HDAC inhibitors (HDACi) exhibit marked antitumor effects in various malignancies. The studies here demonstrate that pan-HDAC inhibitors constitute novel therapeutics versus epithelioid sarcoma. Human ES cells (VAESBJ, HS-ES, Epi-544) were studied in preclinical models to evaluate HDACi effects. Immunoblot and RT-PCR were used...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Lopez, G., Song, Y., Lam, R., Ruder, D., Creighton, C. J., Bid, H. K., Bill, K. L., Bolshakov, S., Zhang, X., Lev, D., Pollock, R. E. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Methylation of KCNA5 Promotes Ewing Sarcoma Proliferation
This study investigates the DNA methylation status of polycomb target gene promoters in Ewing sarcoma tumors and cell lines and observes that the promoters of differentiation genes are frequent targets of CpG-island DNA methylation. In addition, the promoters of ion channel genes are highly differentially methylated in Ewing sarcoma compared with nonmalignant adult tissues. Ion channels regulate a variety of biologic processes, including proliferation, and dysfunction of these channels contributes to tumor pathogenesis. In particular, reduced expression of the voltage-gated Kv1.5 channel has been implicated in tumor progre...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Ryland, K. E., Hawkins, A. G., Weisenberger, D. J., Punj, V., Borinstein, S. C., Laird, P. W., Martens, J. R., Lawlor, E. R. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research