Abstract B09: Myc is required for maintenance of KRasG12D-driven pancreatic cancer and its associated microenvironment
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...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Sodir, N. M., Swigart, L. B., Kortlever, R. M., Littlewood, T. D., Soucek, L., Arends, M. J., Evan, G. I. Tags: Modeling Myc in Mouse: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR08: The N-Myc transcriptional program driving the neuroendocrine prostate cancer phenotype
In conclusion, our findings have the potential to ultimately lead to the identification of a new class of disease specific biomarkers and therapeutic alternatives for this aggressive subgroup of prostate cancer.References:1. Beltran, H., S. Tomlins, et al., Clin Cancer Res, 2014. 20(11): p. 2846-50.2. Wang, W. and J.I. Epstein, Am J Surg Pathol, 2008. 32(1): p. 65-71.3. Palmgren, J.S., S.S. Karavadia, et al., Semin Oncol, 2007. 34(1): p. 22-9.4. Wang, H.T., Y.H. Yao, et al., J Clin Oncol, 2014.5. Beltran, H., D.S. Rickman, et al., Cancer Discovery, 2011. 1(6): p. 487-495.6. Mosquera, J.M., H. Beltran, et al., Neoplasia, 20...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Dardenne, E., Gayert, K., Sboner, A., Cheung, C., Eilers, M., Rubin, M., Beltran, H., Elemento, O., Rickman, D. Tags: Myc and Emerging Biology: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA08: MYC and mitochondrial metabolism in childhood neuroblastoma
Neuroblastoma, which arises from the sympathetic nervous system is one of the most aggressive solid tumors of early childhood. Amplification of the MYCN oncogene has been found in around 30% of neuroblastoma patients and it is associated with rapid tumor progression and poor prognosis. New treatment options are urgently needed for this group of patients. As metabolic adaptations are crucial for cancer cell survival during tumor progression, identifying metabolic discrepancies of aggressive tumors may be central in order to find new treatment strategies. We have recently highlighted the importance MYC driven mitochondrial m...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Arsenian-Henriksson, M. Tags: Myc and Metabolism - Metabolomics: Oral Presentations - Invited Abstracts Source Type: research

Abstract B08: Loss of functional Miz-1 impairs c-Myc-dependent B cell lymphomagenesis
Conclusion: Our data indicate that Miz-1 is required for the efficient development of aggressive c-Myc-driven lymphomas. Miz-1 is probably cooperating with c-Myc in the abnormal transcriptional program that is occuring in lymphoma cells. Therefore, targeting Miz-1 in B-lymphomas could lead to the development of new therapeutic approaches.Citation Format: Julie Ross, René Winkler, Charles Vadnais, Marissa Rashkovan, Christian Kosan, Tarik Möröy. Loss of functional Miz-1 impairs c-Myc-dependent B cell lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy;...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Ross, J., Winkler, R., Vadnais, C., Rashkovan, M., Kosan, C., Moroy, T. Tags: Modeling Myc in Mouse: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A08: Identification of c-MYC SUMOylation by mass spectrometry
The c-MYC transcription factor is a master regulator of many cellular processes and deregulation of this oncogene has been linked to more than 50% of all cancers. In normal cells, MYC is tightly controlled at a number of steps, including at the transcriptional, translational and post-translational levels. Altered regulation at any of these steps can result in deregulated, oncogenic MYC. One well-studied canonical pathway that is known to regulate MYC activity and stability at the post-translational level is the GSK3 pathway. The GSK3-FBXW7 axis regulates MYC via phosphorylation at T58, followed by ubiquitylation of MYC by ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Kalkat, M., Chan, P.-K., Wasylishen, A. R., Srikumar, T., Kim, S. S., Ponzielli, R., Bazett-Jones, D. P., Raught, B., Penn, L. Z. Tags: Myc Function and Phosphorylation - Ubiquitination: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR07: Myc-dependent translation makes an impact: Tailor-made protein expression for cancer development
Our research delineates how the "cancer translatome" can reprogram gene expression at the post-transcriptional level, by controlling the translation of specific subsets of mRNAs during distinct steps of cancer progression. Here, we have genetically engineered a novel mouse model in which two of the most commonly perturbed oncogenes, MYC and KRAS, are stochastically activated in a small number of hepatocytes resulting in a dramatic increase in metastatic tumors, recapitulating the process of liver tumor development in human cancers. Therefore, we have used this model to detail the evolution of gene expression from...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Stumpf, C., Cunningham, T., Ruggero, D. Tags: Therapeutic Translation: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA07: Metabolic reprogramming by MYC: Lessons learned from adenovirus
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 - October 18, 2015 Category: Cancer & Oncology Authors: Christofk, H. Tags: Myc and Metabolism - Metabolomics: Oral Presentations - Invited Abstracts Source Type: research

Abstract B07: Expression of MYCS62A in thymocytes is anti-proliferative, but promotes the later emergence of tumorigenic cells
Oncogenic alterations that promote stability of MYC proteins are common in several human tumor types, and expression of stabilized MYC in mice promotes tumorigenesis from breast, pancreas, and thymus. Mutations that inhibit phosphorylation of T58 in MYC limit proteasomal degradation and enhance S62 phosphorylation and protein stability. Physiologically low expression of MycT58A from the ROSA26 locus (ROSA-MYCT58A) causes robust tumorigenesis, whereas tumor development in ROSA-MYCWT expressing cells is rare. Mice with T cell-specific expression of MYCT58A (LckCre ROSA-MYCT58A) typically succumb to thymomas within six months...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Daniel, C. J., Link, J. M., Byers, S., Sears, R. C. Tags: Modeling Myc in Mouse: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A07: MNT-dependent suppression of branched chain amino acid catabolism: A window into the role of MNT:MAX and MNT:MLX complexes in controlling MYC activity
The MYC family of transcription factors participate in a variety of physiological process and can be oncogenic when dysregulated. A key function of MYC is to reprogram metabolic pathways to meet the biomass needs for both normal the cancer cell proliferation. We previously showed that either too much or too little of the MAX-interacting bHLHZip transcriptional repressor MNT can suppress MYC induced oncogenesis. To begin to investigate the complicated relationship between MYC and MNT, we employed microarray and RNAseq analyses to investigate the gene expression profiles between WT and MNT deficient cells during log phase ce...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Yang, G., Link, J. M., Hurlin, P. J., Hurlin, P. J. Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA06: Recycling Myc to survive stress
Missexpression of Myc family members has been linked to numerous abnormalities ranging from developmental defects to cancer. Indeed there is considerable evidence that Myc expression is controlled at every level of gene regulation, including protein degradation. Recently we found that Myc is targeted by calcium-dependent cytosolic proteases from the calpain family. Unlike proteasomal degradation resulting in complete protein destruction, calpain mediated proteolysis leads to partial cleavage of substrates. While regulated calpain activity is essential for embryonic development and terminal differentiation, aberrant calpain...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Conacci-Sorrell, M., Ngouenet, C., Anderson, S., Eisenman, R. Tags: Myc and Metabolism - Metabolomics: Oral Presentations - Invited Abstracts Source Type: research

Abstract A06: N-MYC regulates mitochondrial dynamics in neuroblastoma via direct interaction with Drp1 and LRRC59
Conclusions: N-Myc amplification in NB increased mitochondrial length as a result of an increase in mitochondrial fusion. While there may be some contribution from transcriptional regulation of the genes involved in mitochondrial dynamics, it appeared that the most significant result of N-Myc overexpression is mislocalization of the fission protein, Drp1. This inability of Drp1 to properly translocate to the mitochondrial surface appeared to be a result of a non-transcriptional effect of N-Myc -- physically inhibiting the interaction of Drp1 with a newly identified protein partner, LRRC59 -- at mitochondrial-ER junctions. ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Casinelli, G., Banerjee, S., Sharma, M., Sims-Lucas, S., Stolz, D., Graves., J. A. Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR05: Targeting of CDK7 inhibits super-enhancer-associated oncogenic programs in MYCN-amplified tumor cells
The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a novel covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Chipumuro, E., Marco, E., Christensen, C. L., Kwiatkowski, N., Zhang, T., Hatheway, C. M., Abraham, B. J., Sharma, B., Yeung, C., Altabef, A., Perez-Atayde, A., Wong, K.-K., Yuan, G.-C., Gray, N. S., Young, R. A., George, R. E. Tags: Myc in Human Cancers: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA05: Targeting MYC-mediated cancer metabolism
Myc, as a transcription factor capable of amplifying gene expression, frequently activates genes involved in cell metabolism to support cell growth and proliferation. Because many metabolic genes are ambiently expressed, it is not surprising in retrospect, that many metabolic genes are targets for Myc-mediated gene expression amplification. Collectively, Myc drives the expression of genes that are involved in glucose uptake, glycolysis, amino acid uptake - particularly glutamine- and catabolism, supporting increased protein synthesis required for a growing cell. In this regard, Myc stimulates many genes involved in nucleot...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Dang, C. V. Tags: Myc and Metabolism - Metabolomics: Oral Presentations - Invited Abstracts Source Type: research

Abstract A05: The mitochondrial RNA polymerase is an essential downstream effector of the MYC oncoprotein
Much of the metabolic reprogramming seen in cancer cells, known as the Warburg effect, is regulated by the MYC oncoprotein. Among MYC-regulated changes are: addiction to exogenous glutamine and increased transcription of the lactate dehydrogenase-A gene. MYC also regulates expression of the cad gene, which encodes three enzymes in the pyrimidine biosynthesis pathway, as well as other enzymes linked to nucleotide biosynthesis. Another MYC-regulated change is increased mitochondrial biogenesis and mitochondrial genome (mtDNA) content, despite a decrease in ATP generation via the mitochondrial electron transport chain (ETC). ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Taylor, A., Zhang, X., Cotney, J., Shadel, G., Cameron, C., McMahon, S. Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA04: Neuroblastoma as a paradigm of MYC(N) driven cancers
Neuroblastoma is an enigmatic childhood cancer with phenotypes ranging from spontaneous regression of seemingly advanced disease to relentless metastatic progression. MYCN amplification was defined as a powerful predictor of metastatic potential and acquisition of therapy resistance in the 1980's, and arguably was the first genomic biomarker utilized in routine clinical practice to stratify therapeutic intensity. While there have been incremental improvements in cure rates over the last three decades, these have come at the cost of a highly complex and intensive chemoradiotherapeutic regimen that leaves survivors with sign...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Maris, J. M. Tags: Myc in Human Cancers: Oral Presentations - Invited Abstracts Source Type: research

Abstract B04: In vivo BioID identifies novel Myc interacting partners
Myc oncoprotein is a major driver of cancer initiation and progression, and thus targeting its activity would mark a key therapeutic advance. In a genetic preclinical mouse model, systemic Myc inhibition using the dominant-negative Myc mutant, termed Omomyc, showed that Ras-driven lung cancer could be eradicated without any harmful long-term effects to the animal. However, developing an anti-cancer agent that directly binds and inhibits Myc has not been possible, to date. Therefore, new strategies are required to inhibit Myc in cancer. Understanding the Myc interactome may unravel novel approaches to target Myc in cancer. ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Dingar, D., Kalkat, M., Chan, P.-K., Bailey, S. D., Srikumar, T., Tu, W. B., Coyaud, E., Ponzielli, R., Kolyar, M., Jurisica, I., Huang, A., Lupien, M., Raught, B., Penn, L. Z. Tags: Modeling Myc in Mouse: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A04: Metabolic reprogramming of MYCN amplified neuroblastoma
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 ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Morrison, M., Khuu, S., Schiffman, J., Cairns, B., Rutter, J., Winge, D., Speleman, F., Stewart, R. Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR03: Serine 62 phosphorylated MYC associates with nuclear lamins and its regulation by CIP2A is essential for proliferation induction in vivo
Targeting MYC function would be highly desirable for hyperproliferative diseases. As MYC itself is refractory to direct chemical inhibition, understanding of the mechanisms determining MYC's transcriptional and proliferation promoting activities in vivo would be critical for generation of alternative targeting strategies. However, despite 30 years of research, it is very poorly documented what post-translational mechanisms control MYC function in vivo. Here we demonstrate for the first time that Lamin A/C association is critical for MYC phosphorylation regulation. MYC phosphorylation at serine 62 enhances MYC recruitment t...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Myant, K., Qiao, X., Halonen, T., Come, C., Laine, A., Partanen, J. I., Ogg, E.-L., Laitera, T., Janghorban, M., Okkeri, J., Klefstrom, J., Sears, R. C., Sansom, O. J., Westermarck, J. Tags: Myc Function and Phosphorylation - Ubiquitination: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA03: Role of MYC in germinal-center development and in lymphomagenesis
Germinal centers (GCs) are transient structures that form in second¬ary lymphoid organs where B cells are selected on the basis of their ability to produce high-affinity antibodies. B cells in the GCs are also the cells of origin for most B cell lymphomas, including Burkitt Lymphoma carrying chromosomal translocations involving c-Myc. After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cell...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Dalla-Favera, R. Tags: Myc in Human Cancers: Oral Presentations - Invited Abstracts Source Type: research

Abstract B03: Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc
The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma, where it is also frequently subject to secondary mutations. Substitutions in codon 58, in particular, stabilize the Myc protein and augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 primes phosphorylation of Thr 58, providing a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, genetic data are missing to address whether Pin1 influences Myc-induced lymphomagenesis. Here, we show that genetic ablation of Pin1 in Eµ-myc transgenic mice st...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: D'Artista, L., Piontini, A., Kress, T., Morelli, M., Verrecchia, A., Doni, M., Campaner, S., Amati, B. Tags: Modeling Myc in Mouse: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A03: Integrative analyses reveal distinct metabolic dysregulation in MYC-driven, basal breast cancer
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, ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Camarda, R., Balakrishnan, S., Zhou, A. Y., Anderton, B., Eyob, H., Kohnz, R., Nomura, D. K., Goga, A. Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR02: Dynamic epigenetic regulation of glioblastoma tumorigenicity through a LSD1-MYC-OLIG2 axis
Glioblastoma is one of the most devastating of human cancers, with near-uniform fatality within two years of diagnosis. Therapeutic failure is thought to be related to small subpopulation of cells that exhibit the properties of self-renewal and tumorigenicity. Understanding how such subpopulations attain and retain these properties remains a central question in oncology. One fundamental issue is whether tumorigenicity exists within a static population of elite cells or whether the capacity is stochastically acquired. To test these models, we assayed the tumorigenicity of single-cell subclones derived from long-terms passag...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Chen, C., Kozono, D., Li, J., Nitta, M., Sampetrean, O., Ng, K., Gonda, D., Kushwaha, D. S., Merzon, D., Ramakrishnan, V., Zhu, S., Zhu, K., Matsui, H., Harismendy, O., Hua, W., Mao, Y., Kwon, C.-H., Ligon, K. L., Saya, H., Carter, B. S., Pizzo, D. P., Va Tags: Myc in Human Cancers: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA02: Dissection of the BRG1 and MYC/MAX biological connection and its use in lung cancer therapeutics
Lung cancer is the first cause of death due to cancer in most western countries, in part because of the low efficacy of most current therapies. In this regard, understanding the genetic architecture of lung malignancies has proven to constitute a reliable strategy to develop novel anticancer agents and foretell response to therapies. Previously, we reported that one third of the lung tumors of the non-small cell lung cancer type (NSCLC) endure inactivation of BRG1, which constitutes the fourth most commonly altered gene in this type of cancer. Interestingly, we also observed that BRG1 inactivation and MYC amplification are...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Sanchez-Cespedes, M. Tags: Myc in Human Cancers: Oral Presentations - Invited Abstracts Source Type: research

Abstract B02: The role of the immune system in sustained tumor regression following oncogene inactivation
The MYC oncogene has been implicated in the pathogenesis of many types of human cancer. The Felsher laboratory uses a conditional Tet-off MYC mouse model to study the formation of tumors in multiple tissue types, such as lymphoma, and has demonstrated that MYC-induced tumorigenesis is reversible. We have found that many cancers are "oncogene addicted" to MYC. Our laboratory has shown that an adaptive T cell-mediated immune response is essential for sustained tumor regression upon MYC inactivation (Rakhra et al, Cancer Cell, 2010). Now, we have found evidence suggesting that upon MYC inactivation in tumors, B cell...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Casey, S. C., Do, R. K., Felsher, D. W. Tags: Modeling Myc in Mouse: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A02: The epigenetic modifier CHAF1A opposes neuroblastoma differentiation via metabolic reprogramming
Background. Neuroblastoma (NB) arises from embryonal neural crest secondary to a block in differentiation and long-term survival inversely correlates with degree of neuronal differentiation. Metabolic rewiring is an important feature of undifferentiated NB tumors. Interestingly, MYCN down regulation precedes differentiation of NB cells induced by retinoic acid (RA) and genetic MYCN silencing leads to neuronal differentiation. We have recently demonstrated a novel function for the histone chaperone CHAF1A in blocking NB differentiation. CHAF1A is a subunit of the Chromatin Assembly Factor-1 (CAF1), which regulates H3K9-trim...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Barbieri, E., Chen, Z., Moreno-Smith, M., Shohet, J. M. Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR01: Long noncoding RNA PVT1 potentiates MYC in human cancers with 8q24 gain
Copy number gain of the 8q24.21 chromosomal region have been a prominent mutation in many human cancers and are associated with poor prognosis. The well-characterized MYC oncogene, which resides in the 8q24.21 region, has been, conventionally, the attractive candidate driving these cancers. However, MYC is often co-gained with an adjacent "gene desert" region. This "gene desert" often encompasses the long non-coding RNA gene PVT1, the CCDC26 gene candidate, and the GSDMC gene. Whether low copy number gain of one or more of these genes drives neoplasia is not known. We used chromosome engineering in mice...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Tseng, Y.-Y., Bagchi, A. Tags: Myc in Human Cancers: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA01: Myc functions within a transcriptional regulatory network
In this talk I will explore the idea that Myc proteins do not act independently, but rather function in the context of a larger network of transcription factors. This network can be considered as having two interconnected branches, each requiring heterodimerization with either Max or the Max-like protein, Mlx. Max forms heterodimers with Myc and Mxd family proteins (including Mnt and Mga), while Mlx heterodimerizes with the large BHLHZ proteins MondoA and ChREBP. A subset of Mxd proteins also heterodimerize with Mlx. Based on our current knowledge of the organization and the functions of its different components, it is pos...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Eisenman, R. Tags: Keynote Presentation: Oral Presentations - Invited Abstracts Source Type: research

Abstract B01: An allelic series of deregulated c-Myc expression interrogates the oncogenicity of distinct Myc levels in lung adenocarcinoma
A plethora of transgenic mouse models have found that c-Myc induces tumors inefficiently and requires cooperating mutations. Acute activation of high levels of Myc induces cellular proliferation, tempered by intrinsic tumor suppression via apoptosis. We hypothesized that low, near physiological, levels of deregulated Myc that fail to invoke tumor suppression pathways, would more effectively initiate sporadic tumors.We previously described the Rosa26lslMycER (R26MER) allele in which deregulated c-Myc is expressed at an endogenous-like level following expression of Cre-recombinase. This c-Myc is fused to a modified estrogen ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Burkhart, D. L., Wilson, C. H., Bywater, M., Kortlever, R., Li, J., Arends, M. J., Littlewood, T. D., Evan, G. I. Tags: Modeling Myc in Mouse: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A01: MYC regulates glutathione depletion and glutamine utilization via miR-18a in vivo
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 glutathi...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Anderton, B., Balakrishnan, A., Balakrishnan, S., Lim, L., Kohnz, R., Nomura, D., Goga, A. Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research

Correction: Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Tags: Correction Source Type: research

Measuring PI3K Activation in Prostate Cancer
Assessing the extent of PI3K pathway activity in cancer is vital to predicting sensitivity to PI3K-targeting drugs, but the best biomarker of PI3K pathway activity in archival tumor specimens is unclear. Here, PI3K pathway activation was assessed, in clinical tissue from 1,021 men with prostate cancers, using multiple pathway nodes that include PTEN, phosphorylated AKT (pAKT), phosphorylated ribosomal protein S6 (pS6), and stathmin. Based on these markers, a 9-point score of PI3K activation was created using the combined intensity of the 4-markers and analyzed its association with proliferation (Ki67), apoptosis (TUNEL), a...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Martin, N. E., Gerke, T., Sinnott, J. A., Stack, E. C., Andren, O., Andersson, S.-O., Johansson, J.-E., Fiorentino, M., Finn, S., Fedele, G., Stampfer, M., Kantoff, P. W., Mucci, L. A., Loda, M. Tags: Signal Transduction Source Type: research

Decreased eIF3e Expression Affects EMT via TGF{beta}
The eIF3e protein is a component of the multisubunit eIF3 complex, which is essential for cap-dependent translation initiation. Decreased eIF3e expression is often observed in breast and lung cancer and has been shown to induce epithelial-to-mesenchymal transition (EMT) in breast epithelial cells by an unknown mechanism. Here, we study the effect of decreased eIF3e expression in lung epithelial cells by creating stable clones of lung epithelial cells (A549) that express an eIF3e-targeting shRNA. Our data indicate that decreased eIF3e expression in lung epithelial cells leads to EMT, as it does in breast epithelial cells. I...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Desnoyers, G., Frost, L. D., Courteau, L., Wall, M. L., Lewis, S. M. Tags: Oncogenes and Tumor Suppressors Source Type: research

Targeting Proline Biosynthesis in Melanoma
This study demonstrates that melanoma cells are sensitive to disruption of proline synthesis and provides a proof-of-concept that the proline synthesis pathway can be therapeutically targeted in melanoma tumors for tumor inhibitory efficacy. Mol Cancer Res; 13(10); 1408–20. ©2015 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Kardos, G. R., Wastyk, H. C., Robertson, G. P. Tags: Oncogenes and Tumor Suppressors Source Type: research

Klotho Structure-Function Relationships in Breast Cancer
Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the β-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure–function relationships governing its tumor suppressor ac...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Ligumsky, H., Rubinek, T., Merenbakh-Lamin, K., Yeheskel, A., Sertchook, R., Shahmoon, S., Aviel-Ronen, S., Wolf, I. Tags: Oncogenes and Tumor Suppressors Source Type: research

YU238259: A Novel Inhibitor of Homology-Dependent DNA Repair
Radiotherapy and DNA-damaging chemotherapy are frequently utilized in the treatment of solid tumors. Innate or acquired resistance to these therapies remains a major clinical challenge in oncology. The development of small molecules that sensitize cancers to established therapies represents an attractive approach to extending survival and quality of life in patients. Here, we demonstrate that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. YU238259 specifically inhibits homology-dependent DNA ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Stachelek, G. C., Peterson-Roth, E., Liu, Y., Fernandez, R. J., Pike, L. R. G., Qian, J. M., Abriola, L., Hoyer, D., Hungerford, W., Merkel, J., Glazer, P. M. Tags: DNA Damage and Repair Source Type: research

Control of eIF2 Function by mTORC2
The mTOR nucleates two complexes, namely mTOR complex 1 and 2 (mTORC1 and mTORC2), which are implicated in cell growth, survival, metabolism, and cancer. Phosphorylation of the α-subunit of translation initiation factor eIF2 at serine 51 (eIF2αS51P) is a key event of mRNA translation initiation and a master regulator of cell fate during cellular stress. Recent studies have implicated mTOR signaling in the stress response, but its connection to eIF2αS51P has remained unclear. Herein, we report that genetic as well as catalytic inhibition of mTORC2 induces eIF2αS51P. On the other hand, the allosteric ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Tenkerian, C., Krishnamoorthy, J., Mounir, Z., Kazimierczak, U., Khoutorsky, A., Staschke, K. A., Kristof, A. S., Wang, S., Hatzoglou, M., Koromilas, A. E. Tags: Cell Death and Survival Source Type: research

Modulation of Downstream Signals of IGFIR by Endoplasmic Reticulum Stress
This study provides a new rationale for further exploration of E2-induced apoptosis to improve clinical benefit. Mol Cancer Res; 13(10); 1367–76. ©2015 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Fan, P., Cunliffe, H. E., Maximov, P. Y., Agboke, F. A., McDaniel, R. E., Zou, X., Ramos, P., Russell, M. L., Jordan, V. C. Tags: Cell Death and Survival Source Type: research

MTHFD2 Is a Novel Anticancer Target
Rapidly proliferating tumors attempt to meet the demands for nucleotide biosynthesis by upregulating folate pathways that provide the building blocks for pyrimidine and purine biosynthesis. In particular, the key role of mitochondrial folate enzymes in providing formate for de novo purine synthesis and for providing the one-carbon moiety for thymidylate synthesis has been recognized in recent studies. We have shown a significant correlation between the upregulation of the mitochondrial folate enzymes, high proliferation rates, and sensitivity to the folate antagonist methotrexate (MTX). Burkitt lymphoma and diffuse large-c...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Tedeschi, P. M., Vazquez, A., Kerrigan, J. E., Bertino, J. R. Tags: Perspective Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Tags: Highlights Source Type: research

MicroRNA and Chondrosarcoma Metastasis
Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeut...
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Sun, X., Charbonneau, C., Wei, L., Chen, Q., Terek, R. M. Tags: Signal Transduction Source Type: research

PKC{epsiv} and Prostate Cancer Bone Metastasis
This study examines the involvement of protein kinase C epsilon (PKC), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKC expression was silenced using shRNA. Interestingly, while PKC depletion had only marginal effects on the proliferative, adhesive, and migratory capacities of PC3-ML cells in vitro or in the growth of xenografts upon s.c. inoculatio...
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Gutierrez-Uzquiza, A., Lopez-Haber, C., Jernigan, D. L., Fatatis, A., Kazanietz, M. G. Tags: Oncogenes and Tumor Suppressors Source Type: research

Analysis of Cancer-Associated KRAS Mutations
KRAS mutations are the most common genetic abnormalities in cancer, but the distribution of specific mutations across cancers and the differential responses of patients with specific KRAS mutations in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specific KRAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)–stimulated GTPase activities, and interactions with...
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Hunter, J. C., Manandhar, A., Carrasco, M. A., Gurbani, D., Gondi, S., Westover, K. D. Tags: Oncogenes and Tumor Suppressors Source Type: research

Prognostic Prediction in Bladder Cancer
This study demonstrates the effectiveness of an E2F4 signature for prognostic prediction of bladder cancer. E2F4 scores for each sample in a bladder cancer expression dataset were calculated by summarizing the relative expression levels of E2F4 target genes identified by ChIP-seq, and then the scores were used to stratify patients into good- and poor-outcome groups. The molecular signature was investigated in a single bladder cancer dataset and then its effectiveness was confirmed in two meta-bladder datasets consisting of specimens from multiple independent studies. These results were consistent in different datasets and ...
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Cheng, C., Varn, F. S., Marsit, C. J. Tags: Genomics Source Type: research

IQGAP1 Negatively Regulates Human Bladder Tumor Growth
This study used gene mutation information from patient-derived bladder tumor specimens to inform the development of a screen used to identify novel tumor growth suppressors. This included identification of the protein IQGAP1 as a potent bladder cancer growth suppressor. Mol Cancer Res; 13(9); 1306–15. ©2015 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Hensel, J., Duex, J. E., Owens, C., Dancik, G. M., Edwards, M. G., Frierson, H. F., Theodorescu, D. Tags: Genomics Source Type: research

MCM Reduction Chemosensitizes PDAC Cells
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is very difficult to treat with conventional chemotherapeutic regimens. Gemcitabine and 5-fluorouracil are used in the management of PDAC and act by indirectly blocking replicative forks. However, these drugs are not highly effective at suppressing disease progression, indicating a need for the development of innovative therapeutic approaches. Recent studies indicate that suppression of the MCM helicase may provide a novel means to sensitize cancer cells to chemotherapeutic agents that inhibit replicative fork progression. Mammalian cells a...
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Bryant, V. L., Elias, R. M., McCarthy, S. M., Yeatman, T. J., Alexandrow, M. G. Tags: DNA Damage and Repair Source Type: research

IK Targeting in Glioblastoma
Ca2+-activated K+ channels, such as BK and IK channels, have been proposed to fulfill pivotal functions in neoplastic transformation, malignant progression, and brain infiltration of glioblastoma cells. Here, the ionizing radiation (IR) effect of IK K+ channel targeting was tested in human glioblastoma cells. IK channels were inhibited pharmacologically by TRAM-34 or genetically by knockdown, cells were irradiated with 6 MV photons and IK channel activity, Ca2+ signaling, cell cycling, residual double-strand breaks, and clonogenic survival were determined. In addition, the radiosensitizing effect of TRAM-34 was analyzed in...
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Stegen, B., Butz, L., Klumpp, L., Zips, D., Dittmann, K., Ruth, P., Huber, S. M. Tags: Cell Death and Survival Source Type: research

VEGFR1 Pseudogene Expression and Function in Colorectal Cancer Cells
This study identifies FLT1P1 antisense as a critical regulator of VEGFR1 and VEGF-A expression in colorectal cancer cells, and highlights its role in regulation of the pathogenesis of colorectal cancer. Implications: The VEGFR1 pseudogene, FLT1P1, is a novel and functional regulator of VEGF signaling and its targeting could be an alternative strategy to modulate its cognate/target gene expression and downstream activity in cancer. Mol Cancer Res; 13(9); 1274–82. ©2015 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Ye, X., Fan, F., Bhattacharya, R., Bellister, S., Boulbes, D. R., Wang, R., Xia, L., Ivan, C., Zheng, X., Calin, G. A., Wang, J., Lu, X., Ellis, L. M. Tags: Cell Death and Survival Source Type: research

The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas
KRAS4B is a highly oncogenic splice variant of the KRAS isoform. It is the only isoform associated with initiation of adenocarcinomas. Insight into why and how KRAS4B can mediate ductal adenocarcinomas, particularly of the pancreas, is vastly important for its therapeutics. Here we point out the overlooked critical role of calmodulin (CaM). Calmodulin selectively binds to GTP-bound K-Ras4B; but not to other Ras isoforms. Cell proliferation and growth require the MAPK (Raf/MEK/ERK) and PI3K/Akt pathways. We propose that Ca2+/calmodulin promote PI3Kα/Akt signaling, and suggest how. The elevated calcium levels clinicall...
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Authors: Nussinov, R., Muratcioglu, S., Tsai, C.-J., Jang, H., Gursoy, A., Keskin, O. Tags: Review Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 13, 2015 Category: Cancer & Oncology Tags: Highlights Source Type: research

Link of K-Ras Mutations to CREB in Tumor Cells
Oncogenic transformation is often associated with an increased expression of the cAMP response element binding (CREB) transcription factor controlling the expression of genes involved in cell proliferation, cell cycle, apoptosis, and tumor development, but a link between K-RASV12-induced transformation and CREB has not yet been determined. Therefore, the constitutive and/or inhibitor-regulated mRNA and protein expression of CREB and signal transduction components and growth properties of parental fibroblasts, K-RASV12-transformed counterparts, shCREB K-RASV12 transfectants and human colon carcinoma cells were determined. I...
Source: Molecular Cancer Research - August 16, 2015 Category: Cancer & Oncology Authors: Steven, A., Heiduk, M., Recktenwald, C. V., Hiebl, B., Wickenhauser, C., Massa, C., Seliger, B. Tags: Signal Transduction Source Type: research