bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A01: MYC regulates glutathione depletion and glutamine utilization via miR-18a in vivo
Authors: Anderton Brittany , Balakrishnan Asha , Balakrishnan Sanjeev , Lim Lionel , Kohnz Rebecca , Nomura Dan , Goga Andrei 
Published: October 2015

Abstract
Recent research suggests that MYC activation in tumor cells leads to a unique metabolic phenotype that is characterized by glutamine addiction and TCA cycle activation. We wish to identify novel metabolic pathways that are altered in MYC-driven cancer in vivo. To that end, we have performed microarray-based transcriptomics and mass-spectrometry-based metabolomics profiling of tumors from a murine model of MYC-driven liver cancer. Using Fisher's exact test, we have identified glutathione metabolism as the most significantly enriched pathway across the two datasets. Notably, both the reduced and oxidized isoforms of glutathione, a major cellular antioxidant, are depleted in tumors relative to naïve control livers. We find that the rate-limiting enzyme of glutathione synthesis, Gclc, is attenuated by a MYC-regulated microRNA miR-18a. Loss of glutathione production is concomitant with increased glutamine conversion into TCA cycle metabolites in vivo. Despite loss of glutathione and another antioxidant, NADPH, our MYC-driven tumors do not exhibit markers of elevated oxidative stress. Instead, they appear to upregulate a host of alternative antioxidant pathways including Vitamin C and thioredoxins. In summary, while it is well established that MYC-driven tumors have increased dependence on glutamine resulting in increased glutamate production, whether MYC also regulates glutamate utilization decisions remains poorly understood. Here we show that MYC can regulate glutamate flux by attenuating glutathione production, shifting glutamate utilization towards the TCA cycle.
Citation Format: Brittany Anderton, Asha Balakrishnan, Sanjeev Balakrishnan, Lionel Lim, Rebecca Kohnz, Dan Nomura, Andrei Goga. MYC regulates glutathione depletion and glutamine utilization via miR-18a in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A01.
Abstract A03: Integrative analyses reveal distinct metabolic dysregulation in MYC-driven, basal breast cancer
Authors: Camarda Roman , Balakrishnan Sanjeev , Zhou Alicia Y. , Anderton Brittany , Eyob Henok , Kohnz Rebecca , Nomura Daniel K. , Goga Andrei 
Published: October 2015

Abstract
Dysregulated metabolism is a hallmark of all human cancers. The observation that tumors display unique changes in metabolism led to the hypothesis that tumors may be dependent upon an altered metabolic state. c-MYC (MYC) is a proto-oncogene and transcription factor activated in many cancers that regulates multiple metabolic pathways. Our lab and others have shown that MYC is activated in a large proportion of basal-like breast cancer, the most aggressive subtype of human breast cancer. However, the role of MYC in basal breast cancer metabolism is largely unknown. No efficacious MYC inhibitor is available for clinical use, however, an alternative treatment strategy is to target cellular pathways required in the context of MYC activation. We hypothesize that basal-like breast cancer harbors distinct, MYC-driven metabolic dysregulation, and that this dysregulation can be targeted therapeutically to induce MYC-dependent synthetic lethality. Utilizing in vitro and in vivo models of MYC-driven and basal breast cancer, including patient-derived cell lines and patient-derived xenograft mouse tumor models, we have performed metabolomic and transcriptomic analyses. We investigate MYC-dependent metabolic dysregulation via integrated analyses of these datasets, and find distinct changes that could reveal essential metabolic pathways for MYC-driven, basal tumorigenesis.
Citation Format: Roman Camarda, Sanjeev Balakrishnan, Alicia Y. Zhou, Brittany Anderton, Henok Eyob, Rebecca Kohnz, Daniel K. Nomura, Andrei Goga. Integrative analyses reveal distinct metabolic dysregulation in MYC-driven, basal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A03.
Abstract A04: Metabolic reprogramming of MYCN amplified neuroblastoma
Authors: Morrison Monique , Khuu Scott , Schiffman Joshua , Cairns Bradley , Rutter Jared , Winge Dennis , Speleman Frank , Stewart Rodney 
Published: October 2015

Abstract
Neuroblastoma (NB) is a highly malignant embryonic tumor of neural crest origin and accounts for 15% of all cancer deaths in children. Amplification of the MYCN oncogene, which occurs in ~25% of patients, is the most reliable marker of metastatic disease and predicts poor outcome. Recent findings show MYCN reprograms NB cell metabolism to promote glycolysis and shunting of glutamate into the TCA cycle, causing dependence on increased levels of TCA intermediates, such as a-KG and succinate. Allelic loss of the short arm of chromosome 1, (1p36) is associated with the vast majority of MYCN amplified NB, and a candidate tumor suppressor gene (TSG) in this region is succinate dehydrogenase subunit B,SDHB, which encodes a core component of the succinate dehydrogenase (SDH) complex, converting succinate to fumarate. We show that MYCN-amplified NB cells, with 1p deletion, have reduced SDHB protein levels and elevated succinate levels. Thus, we are now testing a model that the combined loss of SDH activity with MYCN amplification causes dramatic accumulation of cytosolic succinate, which in turn stabilizes HIF1α to accelerate NB pathogenesis in vivo. To test this model, we have generated mutations in zebrafish sdhb to determine if 1) it is normally required for sympathetic neuron differentiation and 2) cooperates with MYCN to accelerate zebrafish NB in vivo (Zhu et. al, Cancer Cell, 2012). As HIF1a is predicted to be upregulated in SDH-deficient cells, as well as MYCN-amplified NB, we have also generated stable HIF1α transgenic zebrafish lines to directly determine if HIF1α alone is sufficient to drive NB or cooperates with MYCN to accelerate it. The results from our studies of sdhb loss and hif1α gain on peripheral sympathetic nervous system development and NB formation in vivo will be discussed as well as potential therapeutic approaches to target SDH/MYCN-dependent tumors.
Citation Format: Monique Morrison, Scott Khuu, Joshua Schiffman, Bradley Cairns, Jared Rutter, Dennis Winge, Frank Speleman, Rodney Stewart. Metabolic reprogramming of MYCN amplified neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A04.
Abstract A11: Biophysical characterization of the b-HLH-LZ of deltaMax
Authors: Maltais Loïka , Tremblay Cynthia , Bédard Mikaël , Montagne Martin , Lavigne Pierre 
Published: October 2015

Abstract
Myc proteins (N-, L- and c-Myc) are transcriptional regulators with a broad spectrum of target genes. While essential for development, cell growth and proliferation as well as apoptosis, they play a major role in cancer onset and progression when deregulated. Myc protein functions depend on their heterodimerization with Max, another transcriptional regulator capable of forming a homodimer and antagonizing c-Myc transcriptional regulation. Recent studies have shown that c-Myc can control the alternative splicing of Max's pre-messenger RNA to produce a c-terminal truncated isoform called deltaMax. The ratio of deltaMax/WT-Max (p21) in cancer cells correlates with increased malignancy. In addition to producing a shorter gene product, the alternative splicing (exon-inclusion) generates a change in sequence in the LZ. The LZ domain is an integral and crucial part of the b-HLH-LZ motif of Max controlling its homodimerization and specific heterodimerization with c-Myc as well as binding to the E-box sequences found in gene promoters and enhancers. Whereas it has been demonstrated that deltaMax increases c-Myc transcriptional activities, the underlying mechanisms have not been elucidated yet. Here, we provide original insights into such mechanisms. First, we show that contrary to the WT motif, the b-HLH-LZ of deltaMax does not homodimerize. In addition, while the b-HLH-LZ of deltaMax can still heterodimerize with the b-HLH-LZ of c-Myc, it can no longer compete with the binding of the heterodimer to E-box sequences. Taken together, our results demonstrate that deltaMax can maximize the amount of c-Myc bound target gene promoters and enhancers and explain how deltaMax and the ratio of deltaMax/WT-Max (p21) in cancer cells can increase c-Myc oncogenic activities.
Citation Format: Loïka Maltais, Cynthia Tremblay, Mikaël Bédard, Martin Montagne, Pierre Lavigne. Biophysical characterization of the b-HLH-LZ of deltaMax. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A11.
Abstract A14: Epigenetic alterations reactivate a novel mechanism of Myc-induced apoptosis
Authors: Adams Clare M. , Eischen Christine M. 
Published: October 2015

Abstract
Cancer initiation and progression is often driven by dysregulation of the Myc oncoprotein. The tumorigenic consequences of aberrant Myc expression emerge from its potential to broadly regulate gene expression. Alterations in gene expression resulting from specific epigenetic modifications contribute to the Myc oncogenic program to facilitate tumor development. As such, inhibitors targeting a certain class of chromatin-modifying enzymes have demonstrated therapeutic potential in treating malignancies, resulting in selective killing of cancer cells. However, the molecular events underlying the tumor cell-selective apoptosis are incompletely resolved. We determined that inhibition of specific epigenetic-modifying enzymes in cancers of hematopoietic and non-hematopoietic origin relieved the Myc-mediated transcriptional repression of specific genes. This transcriptional switch resulted in Myc-driven upregulation of these genes, which subsequently decreased the expression of crucial pro-survival genes, inducing apoptosis in multiple cancers. Furthermore, we demonstrated that Myc transcriptionally upregulated these genes in normal cells as a means to prevent cellular transformation, revealing a mechanism whereby Myc induces apoptosis independent of the p53 tumor suppressor. Our data reveal a Myc-regulated mechanism of cell death that underlies the apoptotic consequences of inhibiting a class of epigenetic modifiers. This apoptotic mechanism offers new insights that should aid in improving therapies for the 70% of human cancers that have dysregulated MYC.
Note: This abstract was not presented at the conference.
Citation Format: Clare M. Adams, Christine M. Eischen. Epigenetic alterations reactivate a novel mechanism of Myc-induced apoptosis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A14.
Abstract A38: The role of MGA loss-of-function mutations in lung adenocarcinomas
Authors: Zhang Xiaoyang , Francis Joshua , Lin Charles , Rahl Peter , Bradner James , Young Richard 
Published: October 2015

Abstract
MYC activation promotes tumorigenesis in a wide range of tissues. The Cancer Genome Atlas project has recently reported that MGA, encoding a potential suppressor of MYC activity, is significantly mutated in lung adenocarcinomas and the majority of mutations are loss-of-function. Roughly 10% of lung adenocarcinoma cases acquire either MGA loss-of-function mutations or homozygous deletions. Employing functional genomics methodologies, we aimed to characterize the role of MGA mutations in lung adenocarcinoma, with an emphasis on studying their involvement in modulating MYC activity. Using CRISPR knockout technologies, we showed that MGA inactivation induces cellular transformation of primary lung epithelium cells AALE, suggesting that MGA acts as a tumor suppressor. In addition, by performing chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) assays, we showed that MGA competes with MYC for a subset of DNA-binding sites and represses the expression of genes nearby. Finally, we revealed that the gene repression function of MGA is due to its association with the HDAC1/2 complex. The discovery of MGA mutations defines a new pathway in lung adenocarcinoma: the MYC/MAX/MGA pathway. Our study not only illuminates the activity MGA mutant lung adenocarcinomas but also those tumors with amplifications of MYC.
Citation Format: Xiaoyang Zhang, Joshua Francis, Charles Lin, Peter Rahl, James Bradner, Richard Young. The role of MGA loss-of-function mutations in lung adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A38.
Abstract A46: Regulation of genomic Myc binding by Pin1 in serum-stimulated fibroblasts
Authors: Su Yulong , Pelz Carl , Impey Soren , Sears Rosalie 
Published: October 2015

Abstract
The transcription factor Myc's induction of its pro-oncogenic target genes is regulated by Serine62 (S62) phosphorylation and the Pin1 prolyl-isomerase, where pS62-Myc is isomerized at Proline63 by Pin1 and this facilitates its recruitment to select target gene promoters. It is also known that Myc is an early serum response gene that controls cellular transition from quiescence to proliferation. In order to examine the global effects of Pin1 on Myc activity, we have performed unbiased genome-wide RNA-seq and ChIP-seq for Myc in primary murine embryo fibroblasts (MEFs) derived from Pin1 wild-type and knockout mice. The MEFs were serum starved for 72 hours and serum stimulated for 4 hours. Through RNA-seq we have observed a striking blunting of serum responsive genes in the Pin1 null cells. From our highly reproducible ChIP-seq data (6719 regions, IDR&lt;0.1, Pin1 wild-type, stimulated), we found that both the number and magnitude of Myc DNA binding peaks were reduced in the null cells in genes showing blunted serum response. Using functional annotation analysis tools (DAVID and GSEA), we found opposing pathway-enrichments for Myc binding in null versus wild-type cells, with proliferation and migration genes enriched in wild-type cells. Furthermore, binding motif analysis of Myc-binding sites suggested a stronger enrichment of canonical E-box motif (CACGTG) in wild-type cells over null cells. In summary, our study suggested a key role that Pin1 plays in Myc global DNA binding activity.
Citation Format: Yulong Su, Carl Pelz, Soren Impey, Rosalie Sears. Regulation of genomic Myc binding by Pin1 in serum-stimulated fibroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A46.
Abstract A47: Gene regulation by Myc during B cell activation
Authors: Tesi Alessandra , Sabò Arianna , Bianchi Valerio , Morelli Marco , Pelizzola Mattia , Amati Bruno 
Published: October 2015

Abstract
Myc is required for the response of cells to proliferative stimuli, as shown for example in fibroblasts or B-cells. Cellular activation entails the regulation of specific transcriptional programs concomitant with a general increase in RNA production (also termed “amplification”), which will need to be carefully disentangled for a full understanding of the mitogenic response. Upon activation of quiescent fibroblasts with serum, c-myc is rapidly induced, and is required for the subsequent activation of a set of ca. 300 genes (Myc-Dependent Serum Response, or MDSR genes) in the early-mid G1 phase of the cell cycle (1). This is followed by RNA amplification, concomitant with the G1-S transition (2). Deletion of the c-myc gene prior to serum stimulation led to a loss of all of these responses: these data indicated that Myc primarily acts to selectively regulate specific gene programs, with RNA amplification occurring as a secondary consequence (2). This is in apparent contrast with previous studies on B-cells and tumors, in which Myc was proposed to directly drive transcriptional amplification at all active loci (3, 4). Here, we addressed Myc-dependent responses in primary mouse B-cells, based on conditional deletion of c-myc followed by LPS stimulation. Our data indicate that, as in fibroblasts, a discrete set of Myc-dependent genes can be identified in B-cells: the response of these genes occurs prior to general RNA amplification, and is not entirely attributable to overt promoter/enhancer invasion by Myc. Together with our previous studies (see poster by A. Sabò et al.) (2), these data provide a unifying view of Myc' s action in different cell types, with amplification occurring as an indirect effect, following from the action of specific Myc-target genes on cellular physiology and metabolism. Systematic work is needed to unravel which of the numerous Myc-regulated genes are critical in mediating this chain of events.
References:
1. Perna D, et al. (2012) Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts. Oncogene 31, 1695-1709.
2. Sabo A, et al. (2014) Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature 511, 488-492.
3. Nie Z, et al. (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68-79.
4. Lin CY, et al. (2012) Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56-67.
Citation Format: Alessandra Tesi, Arianna Sabò, Valerio Bianchi, Marco Morelli, Mattia Pelizzola, Bruno Amati. Gene regulation by Myc during B cell activation. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A47.
Abstract A48: Gene expression signatures associated with MYC oncogene addiction in lymphoma
Authors: Koch Daniel , Adams Stacey , Gentles Andrew , Anchang Benedict , Sullivan Delaney , Plevritis Sylvia , Felsher Dean 
Published: October 2015

Abstract
c-MYC is a bHLH transcription factor that heterodimerizes with MAX to form an active transcription factor complex that binds to promoter regions across the genome. MYC is a potent oncogene that promotes tumorigenesis in many cell types. Several studies have shown that tumor cells can be dependent on proto-oncogenes such as MYC, a state called “oncogene addiction.” Recent findings have revealed that c-myc amplifies active gene programs, and our group has previously identified a unique MYC transcriptional signature. In an effort to understand how MYC regulates discrete transcriptional programs across the genome we searched for potential cofactors that coordinate with MYC. Using computational approaches we examined several publically available human data sets as well as our own conditional MYC murine model for potential co-factor interactions. We have determined that several Jumonji family members coordinate with MYC expression. Currently, we are using CRISPR/Cas9 mediated disruption of target genes in murine cells to investigate whether these genes have a casual role in MYC oncogene addiction.
Citation Format: Daniel Koch, Stacey Adams, Andrew Gentles, Benedict Anchang, Delaney Sullivan, Sylvia Plevritis, Dean Felsher. Gene expression signatures associated with MYC oncogene addiction in lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A48.
Abstract B09: Myc is required for maintenance of KRasG12D-driven pancreatic cancer and its associated microenvironment
Authors: Sodir Nicole M. , Swigart Lamorna Brown , Kortlever Roderik M. , Littlewood Trevor D. , Soucek Laura , Arends Mark J. , Evan Gerard I. 
Published: October 2015

Abstract
Deregulation of Myc is observed in most, if not all, human cancers making it an attractive therapeutic target. Indeed, recent studies demonstrate that Myc inhibition (via expression of a dominant negative Myc mutant) triggers regression of SV40-driven pancreatic islet tumors and KRasG12D-driven lung tumors in mice. Myc inhibition in insulinomas elicits regression presaged by collapse of the tumor microenvironment and involution of the tumor vasculature. A characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) is an extensive stromal component (desmoplasia) that is thought to contribute to the resistance of PDAC to current therapies. We show that systemic Myc inhibition in KRasG12D-driven mouse PDAC triggers regression of both tumor and its associated desmoplastic stroma, indicating that endogenous Myc function in the tumor cells is required for maintenance of the desmoplastic reaction. Consistent with this, deregulated expression of physiological levels of Myc enhances pancreatic tumor progression and promotes local immune evasion and stromal desmoplasia. Reversal of deregulated Myc activity results in reversion of these features indicating that they are dependent on Myc activity. The ubiquity of Myc in tumor development and maintenance indicates that it serves an essential and non-redundant role, coupling diverse intracellular oncogenic pathways to the tumor microenvironment, and underscoring its credentials as a pharmacological target in cancers driven by different oncogenes and arising in different tissues.
Citation Format: Nicole M. Sodir, Lamorna Brown Swigart, Roderik M. Kortlever, Trevor D. Littlewood, Laura Soucek, Mark J. Arends, Gerard I. Evan. Myc is required for maintenance of KRasG12D-driven pancreatic cancer and its associated microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B09.
Abstract B10: Genome-wide analysis of p53 transcriptional programs in Myc-induced lymphomas
Authors: Tonelli Claudia , Morelli Marco J. , Sabò Arianna , Piontini Andrea , Pelizzola Mattia , Campaner Stefano , Amati Bruno 
Published: October 2015

Abstract
Oncogenic activation of Myc induces cellular transformation and hyper-proliferation, while it activates intrinsic tumor surveillance pathways aimed at restraining the expansion of pre-cancerous cells. All these Myc-induced tumor suppressive mechanisms converge on p53, and loss of p53 activity is the major selected event in lymphomagenesis. Yet, the genetic programs triggered by p53 in tumor suppression have been only partially clarified. Using whole genome mapping of p53 binding and gene expression profiling, we investigated the transcriptional circuitry employed by p53 in suppressing cancer development. We studied the progression of Myc-induced lymphomas in Eµ-myc transgenic mice, as well as the regression of these lymphomas following restoration of p53 function, by either pharmacological or genetic means. We thus identified a set of p53 target genes that are strong candidates for mediating tumor suppression. Currently, we are testing the impact of these new components of the p53 transcriptional program on tumorigenesis with an RNA interference (RNAi)-based functional genetic screen. Altogether our data expand our understanding of the p53 response to Myc-induced oncogenic stress and will hopefully highlight new tumor suppressive mechanisms, paving the way for their therapeutic application.
Citation Format: Claudia Tonelli, Marco J. Morelli, Arianna Sabò, Andrea Piontini, Mattia Pelizzola, Stefano Campaner, Bruno Amati. Genome-wide analysis of p53 transcriptional programs in Myc-induced lymphomas. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B10.