Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion
In this study, we use liquid chromatography–mass spectrometry analysis to demonstrate differences in HS disaccharide content and structure across four patient-derived tumorsphere lines (GBM1, 5, 6, 43) and between two murine tumorsphere lines derived from murine GBM with enrichment of mesenchymal and proneural gene expression (mMES and mPN, respectively) markers. In GBM, the heterogeneous HS content and structure across patient-derived tumorsphere lines suggested diverse functions in the GBM tumor microenvironment. In GBM5 and mPN, elevated expression of sulfatase 2 (SULF2), an extracellular enzyme that alters ligand...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Tran, V. M., Wade, A., McKinney, A., Chen, K., Lindberg, O. R., Engler, J. R., Persson, A. I., Phillips, J. J. Tags: Signal Transduction Source Type: research

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling
ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis, and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here, we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density ...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Roy, R., Dagher, A., Butterfield, C., Moses, M. A. Tags: Signal Transduction Source Type: research

Early-Stage Metastasis Requires Mdm2 and Not p53 Gain of Function
Metastasis of cancer cells to distant organ systems is a complex process that is initiated with the programming of cells in the primary tumor. The formation of distant metastatic foci is correlated with poor prognosis and limited effective treatment options. We and others have correlated Mouse double minute 2 (Mdm2) with metastasis; however, the mechanisms involved have not been elucidated. Here, it is reported that shRNA-mediated silencing of Mdm2 inhibits epithelial–mesenchymal transition (EMT) and cell migration. In vivo analysis demonstrates that silencing Mdm2 in both post-EMT and basal/triple-negative breast ca...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Hauck, P. M., Wolf, E. R., Olivos, D. J., Batuello, C. N., McElyea, K. C., McAtarsney, C. P., Cournoyer, R. M., Sandusky, G. E., Mayo, L. D. Tags: Oncogenes and Tumor Suppressors Source Type: research

Selective MET Kinase Inhibition in MET-Dependent Glioma Models Alters Gene Expression and Induces Tumor Plasticity
The receptor tyrosine kinase (RTK) MET represents a promising tumor target in a subset of glioblastomas. Most RTK inhibitors available in the clinic today, including those inhibiting MET, affect multiple targets simultaneously. Previously, it was demonstrated that treatment with cabozantinib (MET/VEGFR2/RET inhibitor) prolonged survival of mice carrying orthotopic patient-derived xenografts (PDX) of the MET-addicted glioblastoma model E98, yet did not prevent development of recurrent and cabozantinib-resistant tumors. To exclude VEGFR2 inhibition-inflicted blood–brain barrier normalization and diminished tumor distri...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: van den Heuvel, C. N. A. M., Navis, A. C., de Bitter, T., Amiri, H., Verrijp, K., Heerschap, A., Rex, K., Dussault, I., Caenepeel, S., Coxon, A., Span, P. N., Wesseling, P., Hendriks, W., Leenders, W. P. J. Tags: Oncogenes and Tumor Suppressors Source Type: research

Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb
In conclusion, the data indicate that NE rupture in cancer cells is likely due to loss of either the Rb or the p53 pathway. Implications: These findings imply that tumor suppression by Rb and p53 includes the ability to prevent NE rupture, thereby protecting against genome alterations. Mol Cancer Res; 15(11); 1579–86. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Yang, Z., Maciejowski, J., de Lange, T. Tags: Oncogenes and Tumor Suppressors Source Type: research

miR-432 Induces NRF2 Stabilization by Directly Targeting KEAP1
NF-E2–related factor 2 (NRF2) is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1) at the post-translational level. In human cancers, aberrantly stabilized NRF2, by the mutation of either NRF2 or KEAP1 or by the potential inhibition of autophagy, plays a vital role in tumor growth and chemoresistance through the activation of target genes. MicroRNAs (miRNA) are endogenous small noncoding RNAs that can negatively regulate gene expression by interfering with translation and/or stability of target transcripts. However, ...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Akdemir, B., Nakajima, Y., Inazawa, J., Inoue, J. Tags: Oncogenes and Tumor Suppressors Source Type: research

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing
This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res; 15(11); 1558–69. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Maag, J. L. V., Fisher, O. M., Levert-Mignon, A., Kaczorowski, D. C., Thomas, M. L., Hussey, D. J., Watson, D. I., Wettstein, A., Bobryshev, Y. V., Edwards, M., Dinger, M. E., Lord, R. V. Tags: Genomics Source Type: research

Comprehensive Molecular Profiling of Olfactory Neuroblastoma Identifies Potentially Targetable FGFR3 Amplifications
Olfactory neuroblastomas (ONBs), also known as esthesioneuroblastomas, are malignant round-cell tumors that represent up to 5% of sinonasal malignancies. Despite their aggressive course, molecular studies of ONBs have been limited, and targeted therapies are lacking. To identify potential oncogenic drivers and targetable pathways in ONBs, we characterized 20 ONBs, including archived ONBs profiled by targeted, multiplexed PCR (mxPCR)–based DNA next-generation sequencing (NGS) of the coding sequence of over 400 cancer-relevant genes (n = 16), mxPCR-based RNA NGS of 108 target genes (n = 15), and 2 ONBs profiled by comp...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Lazo de la Vega, L., McHugh, J. B., Cani, A. K., Kunder, K., Walocko, F. M., Liu, C.-J., Hovelson, D. H., Robinson, D., Chinnaiyan, A. M., Tomlins, S. A., Harms, P. W. Tags: Genomics Source Type: research

Comprehensive Genomic Profiling of Metastatic Squamous Cell Carcinoma of the Anal Canal
Squamous cell carcinoma of the anal canal (SCCA) is a rare gastrointestinal malignancy with an increasing annual incidence globally. The majority of cases are linked to prior infection with the human papillomavirus (HPV). For patients with metastatic SCCA, no consensus standard treatment exists. Identification of relevant targeted agents as novel therapeutic approaches for metastatic SCCA has been limited by a lack of comprehensive molecular profiling. We performed whole-exome sequencing on tumor–normal pairs from 24 patients with metastatic SCCA. Tumor tissue from 17 additional patients was analyzed using a 263-gene...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Morris, V., Rao, X., Pickering, C., Foo, W. C., Rashid, A., Eterovic, K., Kim, T., Chen, K., Wang, J., Shaw, K., Eng, C. Tags: Genomics Source Type: research

CDK4/6 Inhibition on Glucose and Pancreatic Beta Cell Homeostasis in Young and Aged Rats
Genetic deletion of cyclin-dependent kinase 4 (Cdk4) is associated with pancreatic beta cell loss and glucose dysregulation in rodents. Palbociclib, one of the first selective CDK4/6 inhibitors approved for the treatment of advanced breast cancer, is currently being investigated as an adjuvant treatment in patients with early-stage breast cancer and in a variety of cancers covering a wide-range of patient populations. Hence, longer chronic toxicity studies were necessary to further examine its safety profile. The effects of different doses and duration of palbociclib administration on glucose and beta cell homeostasis in y...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Sacaan, A. I., Thibault, S., Hong, M., Kondegowda, N. G., Nichols, T., Li, R., Rosselot, C., Evering, W., Fenutria, R., Vitsky, A., Brown, T., Finkelstein, M., Garcia-Ocana, A., Khan, N., Stewart, A. F., Vasavada, R. C. Tags: Metabolism Source Type: research

EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma
Ewing sarcoma is a bone malignancy driven by a translocation event resulting in the fusion protein EWS/FLI1 (EF). EF functions as an aberrant and oncogenic transcription factor that misregulates the expression of thousands of genes. Previous work has focused principally on determining important transcriptional targets of EF, as well as characterizing important regulatory partnerships in EF-dependent transcriptional programs. Less is known, however, about EF-dependent metabolic changes or their role in Ewing sarcoma biology. Therefore, the metabolic effects of silencing EF in Ewing sarcoma cells were determined. Metabolomic...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Tanner, J. M., Bensard, C., Wei, P., Krah, N. M., Schell, J. C., Gardiner, J., Schiffman, J., Lessnick, S. L., Rutter, J. Tags: Metabolism Source Type: research

EGFR Mutations Compromise Hypoxia-Associated Radiation Resistance through Impaired Replication Fork-Associated DNA Damage Repair
This study demonstrates that within an altered DNA damage response of hypoxic NSCLC cells, mutant EGFR expression, or EGFR blockade by cetuximab exerts a synthetic lethality effect and significantly compromises radiation resistance in hypoxic tumor cells. Mol Cancer Res; 15(11); 1503–16. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Saki, M., Makino, H., Javvadi, P., Tomimatsu, N., Ding, L.-H., Clark, J. E., Gavin, E., Takeda, K., Andrews, J., Saha, D., Story, M. D., Burma, S., Nirodi, C. S. Tags: DNA Damage and Repair Source Type: research

Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ER{alpha}-negative Breast Cancers to Tamoxifen through ER{alpha} Reexpression
Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple-negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ERα in TNBC. KX-01 is a peptide substrate–targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body w...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Anbalagan, M., Sheng, M., Fleischer, B., Zhang, Y., Gao, Y., Hoang, V., Matossian, M., Burks, H. E., Burow, M. E., Collins-Burow, B. M., Hangauer, D., Rowan, B. G. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/{beta}-catenin Signaling
Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/&...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Emons, G., Spitzner, M., Reineke, S., Möller, J., Auslander, N., Kramer, F., Hu, Y., Beissbarth, T., Wolff, H. A., Rave-Fränk, M., Hessmann, E., Gaedcke, J., Ghadimi, B. M., Johnsen, S. A., Ried, T., Grade, M. Tags: Cell Death and Survival Source Type: research

Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities
This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469–80. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Magani, F., Peacock, S. O., Rice, M. A., Martinez, M. J., Greene, A. M., Magani, P. S., Lyles, R., Weitz, J. R., Burnstein, K. L. Tags: Cell Death and Survival Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition
This study identifies signaling pathways that contribute to the tissue-reconstructing capacity of colon CSCs and suggests that clinically used drugs could be repurposed to improve unresectable colon cancers. Mol Cancer Res; 15(10); 1455–66. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Ishida, R., Koyanagi-Aoi, M., Oshima, N., Kakeji, Y., Aoi, T. Tags: Signal Transduction Source Type: research

EGFR Downregulation after Anti-EGFR Therapy Predicts the Antitumor Effect in Colorectal Cancer
This report clearly demonstrates that anti-EGFR mAb facilitates internalization and subsequent degradation of EGFRs in lysosomes, which is an important determinant of the efficacy of anti-EGFR mAb treatment for colorectal cancer. Mol Cancer Res; 15(10); 1445–54. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Okada, Y., Kimura, T., Nakagawa, T., Okamoto, K., Fukuya, A., Goji, T., Fujimoto, S., Sogabe, M., Miyamoto, H., Muguruma, N., Tsuji, Y., Okahisa, T., Takayama, T. Tags: Signal Transduction Source Type: research

BRAF-inhibitor Associated MEK Mutations Increase RAF-Dependent and -Independent Enzymatic Activity
This study suggests that alternate modes of target inhibition, such as ERK inhibition, will be required to effectively treat tumors harboring these MEK1/2-resistant alleles. Mol Cancer Res; 15(10); 1431–44. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Emery, C. M., Monaco, K.-A., Wang, P., Balak, M., Freeman, A., Meltzer, J., Delach, S. M., Rakiec, D., Ruddy, D. A., Korn, J. M., Haling, J., Acker, M. G., Caponigro, G. Tags: Signal Transduction Source Type: research

Inhibition of Ciliogenesis Promotes Hedgehog Signaling, Tumorigenesis, and Metastasis in Breast Cancer
This study identifies inhibition of ciliogenesis as an important event for activation of Hedgehog signaling and progression of breast cancer to a more aggressive, metastatic disease. Implications: These findings change the way we understand how cancer cells turn on a critical signaling pathways and a provide rationale for developing novel therapeutic approaches to target noncanonical Hedgehog signaling for the treatment of breast cancer. Mol Cancer Res; 15(10); 1421–30. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Hassounah, N. B., Nunez, M., Fordyce, C., Roe, D., Nagle, R., Bunch, T., McDermott, K. M. Tags: Signal Transduction Source Type: research

Molecular Effects of Stromal-Selective Targeting by uPAR-Retargeted Oncolytic Virus in Breast Cancer
The tumor microenvironment (TME) is a relevant target for novel biological therapies. MV-m-uPA and MV-h-uPA are fully retargeted, species-specific, oncolytic measles viruses (MV) directed against murine or human urokinase receptor (PLAUR/uPAR), expressed in tumor and stromal cells. The effects of stromal-selective targeting by uPAR-retargeted MVs were investigated. In vitro infection, virus-induced GFP expression, and cytotoxicity by MV-h-uPA and MV-m-uPA were demonstrated in human and murine cancer cells and cancer-associated fibroblasts in a species-specific manner. In a murine fibroblast/human breast cancer 3D coculture...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Jing, Y., Chavez, V., Ban, Y., Acquavella, N., El-Ashry, D., Pronin, A., Chen, X., Merchan, J. R. Tags: Oncogenes and Tumor Suppressors Source Type: research

p120-Catenin Downregulation and PIK3CA Mutations Cooperate to Induce Invasion through MMP1 in HNSCC
In conclusion, this study demonstrates that P120CTN downregulation and PIK3CA mutations promote MMP1-driven invasion, providing a potential novel target for limiting metastasis in HNSCC. Implications: Because of its role in invasion, MMP1 represents a novel, potential target for limiting metastasis in a subset of HNSCCs with P120CTN downregulation and PIK3CA mutations. Mol Cancer Res; 15(10); 1398–409. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Kidacki, M., Lehman, H. L., Green, M. V., Warrick, J. I., Stairs, D. B. Tags: Oncogenes and Tumor Suppressors Source Type: research

Homeobox Transcription Factor NKX2-1 Promotes Cyclin D1 Transcription in Lung Adenocarcinomas
The known oncogene cyclin D1 (CCND1) participates in progression of the cell cycle from G1 to S-phase. Expression of cyclin D1 is frequently promoted in multiple human cancers including non–small cell lung cancer (NSCLC). However, a relationship between cyclin D1 expression and the prognosis of NSCLC has not been confirmed. NKX2-1 is a homeobox transcription factor involved in pulmonary development as a differentiation-promoting factor. In NSCLC, it acts as a metastasis suppressor and correlates with a good prognosis. Here, NKX2-1–binding motifs were identified in the cyclin D1 promoter, but it has not been cla...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Harada, M., Sakai, S., Ohhata, T., Kitagawa, K., Mikamo, M., Nishimoto, K., Uchida, C., Niida, H., Kotake, Y., Sugimura, H., Suda, T., Kitagawa, M. Tags: Oncogenes and Tumor Suppressors Source Type: research

Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-25-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the β1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) b...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Hassani, Z., Saleh, A., Turpault, S., Khiati, S., Morelle, W., Vignon, J., Hugnot, J.-P., Uro-Coste, E., Legrand, P., Delaforge, M., Loiseau, S., Clarion, L., Lecouvey, M., Volle, J.-N., Virieux, D., Pirat, J.-L., Duffau, H., Bakalara, N. Tags: Oncogenes and Tumor Suppressors Source Type: research

ERR{alpha} Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1{alpha}-Elevated Melanomas
The uncontrolled growth of tumors provides metabolic dependencies that can be harnessed for therapeutic benefit. Although tumor cells exhibit these increased metabolic demands due to their rapid proliferation, these metabolic processes are general to all cells, and furthermore, targeted therapeutic intervention can provoke compensatory adaptation that alters tumors' characteristics. As an example, a subset of melanomas depends on the transcriptional coactivator PGC1α function to sustain their mitochondrial energy-dependent survival. However, selective outgrowth of resistant PGC1α-independent tumor cells becomes...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Luo, C., Balsa, E., Thomas, A., Hatting, M., Jedrychowski, M., Gygi, S. P., Widlund, H. R., Puigserver, P. Tags: Metabolism Source Type: research

Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC
This report identifies a robust list of 22 candidate driver genes that are epigenetically regulated in lung cancer; such genes may complement the known mutational drivers. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/10/1354/F1.large.jpg. Mol Cancer Res; 15(10); 1354–65. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Horie, M., Kaczkowski, B., Ohshima, M., Matsuzaki, H., Noguchi, S., Mikami, Y., Lizio, M., Itoh, M., Kawaji, H., Lassmann, T., Carninci, P., Hayashizaki, Y., Forrest, A. R. R., Takai, D., Yamaguchi, Y., Micke, P., Saito, A., Nagase, T. Tags: Genomics Source Type: research

FOXC1 Regulates FGFR1 Isoform Switching to Promote Invasion Following TGF{beta}-Induced EMT
Epithelial-to-mesenchymal transition (EMT) is an important physiologic process that drives tissue formation during development, but also contributes to disease pathogenesis, including fibrosis and cancer metastasis. Elevated expression of the FOXC1 transcription factor has been detected in several metastatic cancers that have undergone EMT. Therefore, mechanistic insight into the role of FOXC1 in the initiation of the EMT process was sought. It was determined that although Foxc1 transcript expression was elevated following TGFβ1-induced EMT of NMuMG cells, FOXC1 was not required for this induction. RNA sequencing reve...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Hopkins, A., Coatham, M. L., Berry, F. B. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer
This study identifies a class of genes, Interferon (IFN)-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors. Ligand-independent regulation of ISGs was also observed, as basal transcript levels were markedly higher in cells with PR knockdown. PR repressed ISG transcription in response to IFN treatment, the canonical mechanism through which these genes are activated. Liganded PR is robustly recruited to enhancer regions of...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Walter, K. R., Goodman, M. L., Singhal, H., Hall, J. A., Li, T., Holloran, S. M., Trinca, G. M., Gibson, K. A., Jin, V. X., Greene, G. L., Hagan, C. R. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Tuberin Regulates Prostaglandin Receptor-Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells
In this study, we identify upregulation of EP3 (PTGER3) expression in TSC2-deficient cells, TSC renal angiomyolipomas, lymphangioleiomyomatosis lung nodules, and epileptic brain tubers. TSC2 negatively regulated EP3 expression via Rheb in a rapamycin-insensitive manner. The EP3 antagonist, L-798106, selectively suppressed the viability of TSC2-deficient cells in vitro and decreased the lung colonization of TSC2-deficient cells. Collectively, these data reveal a novel function of TSC2 and Rheb in the regulation of EP3 expression and cell viability. Implications: Therapeutic targeting of an aberrant PGE2-EP3 signaling axis m...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Li, C., Liu, X., Liu, Y., Zhang, E., Medepalli, K., Masuda, K., Li, N., Wikenheiser-Brokamp, K. A., Osterburg, A., Borchers, M. T., Kopras, E. J., Plas, D. R., Sun, J., Franz, D. N., Capal, J. K., Mays, M., Sun, Y., Kwiatkowski, D. J., Alayev, A., Holz, M Tags: Cell Death and Survival Source Type: research

Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells
The oncogenic activation of the ETS-related gene (ERG) due to gene fusions is present in over half of prostate cancers in Western countries. Because of its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for prostate cancer. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified, confirming that NOTCH factors are direct transcriptional targets of ERG. Inhibition of ERG in TMPRSS2-ERG–positive VCaP cells led to decreased levels of NOTC...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Mohamed, A. A., Tan, S.-H., Xavier, C. P., Katta, S., Huang, W., Ravindranath, L., Jamal, M., Li, H., Srivastava, M., Srivatsan, E. S., Sreenath, T. L., McLeod, D. G., Srinivasan, A., Petrovics, G., Dobi, A., Srivastava, S. Tags: Cell Death and Survival Source Type: research

A Massively Parallel Fluorescence Assay to Characterize the Effects of Synonymous Mutations on TP53 Expression
In this reporter context, several mutations within the exon caused strong expression changes including mutations that may cause potential gain or loss of function. Further analysis indicates that these effects are largely attributed to errors in splicing, including exon skipping, intron inclusion, and exon truncation, resulting from mutations both at exon–intron junctions and within the body of the exon. These mutations are found at extremely low frequencies in healthy populations and are enriched a few-fold in cancer genomes, suggesting that some of them may be driver mutations in TP53. This assay provides a general...
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Bhagavatula, G., Rich, M. S., Young, D. L., Marin, M., Fields, S. Tags: Rapid Impact Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

Augmented TME O-GlcNAcylation Promotes Tumor Proliferation through the Inhibition of p38 MAPK
O-GlcNAcylation is a dynamic O-linked glycosylation event that plays a crucial role in regulating cellular signaling. Recent studies indicate that increased O-GlcNAcylation is a general feature in cancer and contributes to various cancer phenotypes, including cell proliferation, survival, invasion, metastasis, and energy metabolism. However, the role of O-GlcNAcylation in the tumor microenvironment (TME) is not fully elucidated. Here, B16 melanoma cells were subcutaneously transplanted into O-GlcNAc transferase transgenic (Ogt-Tg) mice exhibiting elevated O-GlcNAcylation to examine the effect of O-GlcNAcylation in the TME ...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Moriwaki, K., Asahi, M. Tags: Signal Transduction Source Type: research

MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation
This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma. Mol Cancer Res; 15(9); 1275–86. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Liu, H., Sun, Q., Sun, Y., Zhang, J., Yuan, H., Pang, S., Qi, X., Wang, H., Zhang, M., Zhang, H., Yu, C., Gu, C. Tags: Signal Transduction Source Type: research

KITD816V Induces SRC-Mediated Tyrosine Phosphorylation of MITF and Altered Transcription Program in Melanoma
This study demonstrates that an oncogenic tyrosine kinase mutant, KITD816V, can alter the transcriptional program of the transcription factor MITF in melanoma Mol Cancer Res; 15(9); 1265–74. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Phung, B., Kazi, J. U., Lundby, A., Bergsteinsdottir, K., Sun, J., Goding, C. R., Jönsson, G., Olsen, J. V., Steingrimsson, E., Rönnstrand, L. Tags: Oncogenes and Tumor Suppressors Source Type: research

IKK{beta}-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent
IKKβ (encoded by IKBKB) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the NF-B pathway. IKKβ exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that IKBKB gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKβ in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKβ in the basal skin layer. IKKβ overexpression resulted in a stri...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Page, A., Bravo, A., Suarez-Cabrera, C., Alameda, J. P., Casanova, M. L., Lorz, C., Segrelles, C., Segovia, J. C., Paramio, J. M., Navarro, M., Ramirez, A. Tags: Oncogenes and Tumor Suppressors Source Type: research

Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG
This study shows that H3.3K27M mutation and PDGF signaling act in concert to accelerate gliomagenesis in a genetic mouse model and identifies repression of p16 tumor suppressor as a target of H3.3K27M, highlighting the G1–S cell-cycle transition as a promising therapeutic avenue. Mol Cancer Res; 15(9); 1243–54. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Cordero, F. J., Huang, Z., Grenier, C., He, X., Hu, G., McLendon, R. E., Murphy, S. K., Hashizume, R., Becher, O. J. Tags: Oncogenes and Tumor Suppressors Source Type: research

PPAR{delta} Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC
This study provides novel insight into the mechanism underlying sorafenib resistance and a potential therapeutic strategy targeting PPAR in advanced hepatocellular carcinoma. Mol Cancer Res; 15(9); 1230–42. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Kim, M.-J., Choi, Y.-K., Park, S. Y., Jang, S. Y., Lee, J. Y., Ham, H. J., Kim, B.-G., Jeon, H.-J., Kim, J.-H., Kim, J.-G., Lee, I.-K., Park, K.-G. Tags: Metabolism Source Type: research

Real-Time Transferrin-Based PET Detects MYC-Positive Prostate Cancer
Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected huma...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Aggarwal, R., Behr, S. C., Paris, P. L., Truillet, C., Parker, M. F. L., Huynh, L. T., Wei, J., Hann, B., Youngren, J., Huang, J., Premasekharan, G., Ranatunga, N., Chang, E., Gao, K. T., Ryan, C. J., Small, E. J., Evans, M. J. Tags: Metabolism Source Type: research

The Landscape of Isoform Switches in Human Cancers
This study indicates that isoform switches with predicted functional consequences are common and important in dysfunctional cells, which in turn means that gene expression should be analyzed at the isoform level. Mol Cancer Res; 15(9); 1206–20. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Vitting-Seerup, K., Sandelin, A. Tags: Genomics Source Type: research

Normal and Cancerous Tissues Release Extrachromosomal Circular DNA (eccDNA) into the Circulation
Cell-free circulating linear DNA is being explored for noninvasive diagnosis and management of tumors and fetuses, the so-called liquid biopsy. Previously, we observed the presence of small extrachromosomal circular DNA (eccDNA), called microDNA, in the nuclei of mammalian tissues and cell lines. Now, we demonstrate that cell-free microDNA derived from uniquely mapping regions of the genome is detectable in plasma and serum from both mice and humans and that they are significantly longer (30%–60%>250 bases) than cell-free circulating linear DNA (~150 bases). Tumor-derived human microDNA is detected in the mouse ci...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Kumar, P., Dillon, L. W., Shibata, Y., Jazaeri, A. A., Jones, D. R., Dutta, A. Tags: Genomics Source Type: research

NR4A2 Promotes DNA Double-strand Break Repair Upon Exposure to UVR
Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV lesions can lead to several complex phenomena, such as the formation of DNA double-strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signaling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV lesion by mechanisms requiring post-t...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Yin, K., Chhabra, Y., Tropee, R., Lim, Y. C., Fane, M., Dray, E., Sturm, R. A., Smith, A. G. Tags: DNA Damage and Repair Source Type: research

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex
This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response. Mol Cancer Res; 15(9); 1173–83. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Han, X., Ranganathan, P., Tzimas, C., Weaver, K. L., Jin, K., Astudillo, L., Zhou, W., Zhu, X., Li, B., Robbins, D. J., Capobianco, A. J. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Inhibition of the Cell Death Pathway in Nonalcoholic Steatohepatitis (NASH)-Related Hepatocarcinogenesis Is Associated with Histone H4 lysine 16 Deacetylation
Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers, and its incidence is steadily increasing worldwide. Recent epidemiologic findings have suggested that the increased incidence of HCC is associated with obesity, type II diabetes mellitus, and nonalcoholic steatohepatitis (NASH); however, the mechanisms and the molecular pathogenesis of NASH-related HCC are not fully understood. To elucidate the underlying mechanisms of the development of NASH-related HCC, we investigated the hepatic transcriptomic and histone modification profiles in Stelic Animal Model mice, the first animal model of NASH-related ...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: de Conti, A., Dreval, K., Tryndyak, V., Orisakwe, O. E., Ross, S. A., Beland, F. A., Pogribny, I. P. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) Antibody
Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photoabsorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG1 anti-PSMA monoclonal antibody (mAb), conjugated to the photoabsorber, IR700DX, in a PSMA-expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR light in ...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Nagaya, T., Nakamura, Y., Okuyama, S., Ogata, F., Maruoka, Y., Choyke, P. L., Kobayashi, H. Tags: Cell Death and Survival Source Type: research

Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase
This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets. Mol Cancer Res; 15(9); 1138–52. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Lerman, I., Garcia-Hernandez, M. d. l. L., Rangel-Moreno, J., Chiriboga, L., Pan, C., Nastiuk, K. L., Krolewski, J. J., Sen, A., Hammes, S. R. Tags: Cell Death and Survival Source Type: research

Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution
High-throughput genomic technologies have revealed a remarkably complex portrait of intratumor heterogeneity in cancer and have shown that tumors evolve through a reiterative process of genetic diversification and clonal selection. This discovery has challenged the classical paradigm of clonal dominance and brought attention to subclonal tumor cell populations that contribute to the cancer phenotype. Dynamic evolutionary models may explain how these populations grow within the ecosystem of tissues, including linear, branching, neutral, and punctuated patterns. Recent evidence in breast cancer favors branching and punctuate...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Gupta, R. G., Somer, R. A. Tags: Review Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

eIF2{alpha} Phosphorylation Mediates IL24-Induced Apoptosis through Inhibition of Translation
IL24 is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor-suppressor activities of IL24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. Supra-physiologic activation and/or overexpression of translation initiation factors are implicated in the initiation and progression of cancer animal models as well as a subset of human cancers. Activation and/or overexpression of translation initiation factors correlate with aggressiveness of cancer and poor prognosis. Two rate-limiting translation initiation complexes, the ternary complex...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Persaud, L., Zhong, X., Alvarado, G., Do, W., Dejoie, J., Zybtseva, A., Aktas, B. H., Sauane, M. Tags: Signal Transduction Source Type: research

Role of Rac1 Pathway in Epithelial-to-Mesenchymal Transition and Cancer Stem-like Cell Phenotypes in Gastric Adenocarcinoma
In conclusion, Rac1 promotes the EMT program in gastric adenocarcinoma and the acquisition of a CSC state. Rac1 inhibition in gastric adenocarcinoma cells blocks EMT and CSC phenotypes, and thus may prevent metastasis and augment chemotherapy. Implications: In gastric adenocarcinoma, therapeutic targeting of the Rac1 pathway may prevent or reverse EMT and CSC phenotypes that drive tumor progression, metastasis, and chemotherapy resistance. Mol Cancer Res; 15(8); 1106–16. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Yoon, C., Cho, S.-J., Chang, K. K., Park, D. J., Ryeom, S. W., Yoon, S. S. Tags: Signal Transduction Source Type: research