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