Combined AURKA and H3K9 Methyltransferase Targeting Inhibits Cell Growth By Inducing Mitotic Catastrophe
The current integrative pathobiologic hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation–based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in three-dimensional spheroids and organoids. The combination also reduces the growth of PDAC xenog...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Mathison, A., Salmonson, A., Missfeldt, M., Bintz, J., Williams, M., Kossak, S., Nair, A., de Assuncao, T. M., Christensen, T., Buttar, N., Iovanna, J., Huebert, R., Lomberk, G. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Therapeutic Targeting of PTK7 is Cytotoxic in Atypical Teratoid Rhabdoid Tumors
Novel discoveries involving the evaluation of potential therapeutics are based on newly identified molecular targets for atypical teratoid rhabdoid tumors (ATRT), which are the most common form of infantile brain tumors. Central nervous system ATRTs are rare, aggressive, and fast growing tumors of the brain and spinal cord and carry a very poor prognosis. Currently, the standard of care for ATRT patients is based on surgical resection followed by systemic chemotherapy and radiotherapy, which result in severe side effects. As protein tyrosine kinases have proven to be actionable targets that reduce tumor growth in a number ...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Messerli, S. M., Hoffman, M. M., Gnimpieba, E. Z., Bhardwaj, R. D. Tags: Cell Death and Survival Source Type: research

IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors
In conclusion, IGH/MYC–positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies. Implications: This study postulates that IGH/MYC–induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpg. Mol Cancer Res; 15(8); 967–72. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Maifrede, S., Martin, K., Podszywalow-Bartnicka, P., Sullivan-Reed, K., Langer, S. K., Nejati, R., Dasgupta, Y., Hulse, M., Gritsyuk, D., Nieborowska-Skorska, M., Lupey-Green, L. N., Zhao, H., Piwocka, K., Wasik, M. A., Tempera, I., Skorski, T. Tags: Rapid Impact Source Type: research

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

Novel Insights into Gastric Cancer: Methylation of R-spondins and Regulation of LGR5 by SP1
This report identifies a regulatory mechanism of LGR5 expression in gastric carcinogenesis, with SP1 as an important component of the transcriptional complex and LGR5 activity, which is modulated by its ligands RSPO1 and RSPO2, whose expression is modulated by methylation. Visual Overview: http://mcr.aacrjournals.org/content/15/6/776/F1.large.jpg. Mol Cancer Res; 15(6); 776–85. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Wilhelm, F., Simon, E., Böger, C., Behrens, H.-M., Krüger, S., Röcken, C. Tags: Signal Transduction Source Type: research

INPP4B and PTEN Loss Leads to PI-3,4-P2 Accumulation and Inhibition of PI3K in TNBC
Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients, and still lacks an effective targeted therapy. Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer. Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4'-phosphate of phosphatidylinositol-(3, 4)-bisphosphate (PI-3,4-P2), creating phosphatidylinositol-3-phosphate. There is debate concer...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Reed, D. E., Shokat, K. M. Tags: Signal Transduction Source Type: research

Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression
This study demonstrates a role for PS and TAM receptors in the regulation of PD-L1 on cancer cells. Mol Cancer Res; 15(6); 753–64. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Kasikara, C., Kumar, S., Kimani, S., Tsou, W.-I., Geng, K., Davra, V., Sriram, G., Devoe, C., Nguyen, K.-Q. N., Antes, A., Krantz, A., Rymarczyk, G., Wilczynski, A., Empig, C., Freimark, B., Gray, M., Schlunegger, K., Hutchins, J., Kotenko, S. V., Birge, Tags: Signal Transduction Source Type: research

Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1
In conclusion, robust and ubiquitous expression of DCLK1 was first demonstrated here in human PNET tissue specimens and cells. DCLK1 characterized the PNET cell behavior, inducing p-FAK/SLUG-mediated EMT. These findings suggest the possibility of developing novel therapeutic strategies against PNETs by targeting DCLK1. Implications: Evidence here reveals that human PNETs diffusely and robustly express the cancer stem cell marker DCLK1, which drives SLUG-mediated EMT, and suggests that NETs share biological features for druggable targets with other tumors, including neuroblastoma that also highly expresses DCLK1. Mol Cancer...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Ikezono, Y., Koga, H., Akiba, J., Abe, M., Yoshida, T., Wada, F., Nakamura, T., Iwamoto, H., Masuda, A., Sakaue, T., Yano, H., Tsuruta, O., Torimura, T. Tags: Signal Transduction Source Type: research

The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53
The APOBEC3 (A3) family of proteins are DNA cytidine deaminases that act as sentinels in the innate immune response against retroviral infections and are responsive to IFN. Recently, a few A3 genes were identified as potent enzymatic sources of mutations in several human cancers. Using human cancer cells and lymphocytes, we show that under stress conditions and immune challenges, all A3 genes are direct transcriptional targets of the tumor suppressor p53. Although the expression of most A3 genes (including A3C and A3H) was stimulated by the activation of p53, treatment with the DNA-damaging agent doxorubicin or the p53 sta...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Menendez, D., Nguyen, T.-A., Snipe, J., Resnick, M. A. Tags: Oncogenes and Tumor Suppressors Source Type: research

Hypoxia Selectively Enhances Integrin {alpha}5{beta}1 Receptor Expression in Breast Cancer to Promote Metastasis
Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate th...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Ju, J. A., Godet, I., Ye, I. C., Byun, J., Jayatilaka, H., Lee, S. J., Xiang, L., Samanta, D., Lee, M. H., Wu, P.-H., Wirtz, D., Semenza, G. L., Gilkes, D. M. Tags: Oncogenes and Tumor Suppressors Source Type: research

Atorvastatin Decreases HBx-Induced Phospho-Akt in Hepatocytes via P2X Receptors
Hepatocellular carcinoma (HCC) is rated as the fifth most common malignancy and third in cancer-related deaths worldwide. Statins, HMG-CoA reductase inhibitors, are potent cholesterol-lowering drugs, and recent epidemiologic evidence suggests that statins prevent aggressive HCC development. Previous experiments revealed that statins downregulate phosphorylated Akt (pAkt). Here, it is demonstrated that atorvastatin decreases nuclear pAkt levels in pancreatic and lung cancer cell lines within minutes, and this rapid effect is mediated by the purinergic P2X receptors. Akt is upregulated by hepatitis viruses and has oncogenic ...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Ghalali, A., Martin-Renedo, J., Högberg, J., Stenius, U. Tags: Oncogenes and Tumor Suppressors Source Type: research

Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable, Left-Sided Colon Cancers with Wild-type RAS/RAF and Better Overall Survival
Here, comprehensive analysis was performed on the molecular and clinical features of colorectal carcinoma harboring chromosome 20q amplification. Tumor and normal DNA from patients with advanced colorectal carcinoma underwent next-generation sequencing via MSK-IMPACT, and a subset of case samples was subjected to high-resolution microarray (Oncoscan). Relationships between genomic copy number and transcript expression were assessed with The Cancer Genome Atlas (TCGA) colorectal carcinoma data. Of the colorectal carcinoma patients sequenced (n = 401) with MSK-IMPACT, 148 (37%) had 20q gain, and 30 (7%) had 20q amplification...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Ptashkin, R. N., Pagan, C., Yaeger, R., Middha, S., Shia, J., O'Rourke, K. P., Berger, M. F., Wang, L., Cimera, R., Wang, J., Klimstra, D. S., Saltz, L., Ladanyi, M., Zehir, A., Hechtman, J. F. Tags: Oncogenes and Tumor Suppressors Source Type: research

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) an...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Lal, S., Cheung, E. C., Zarei, M., Preet, R., Chand, S. N., Mambelli-Lisboa, N. C., Romeo, C., Stout, M. C., Londin, E., Goetz, A., Lowder, C. Y., Nevler, A., Yeo, C. J., Campbell, P. M., Winter, J. M., Dixon, D. A., Brody, J. R. Tags: Genomics Source Type: research

Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways
This study provides novel insight into tumor-derived microvesicles as carriers of oncogenic protein–coding messages that can potentially jeopardize cell-directed therapy, and spread to other compartments of the body. Mol Cancer Res; 15(6); 683–95. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Milani, G., Lana, T., Bresolin, S., Aveic, S., Pasto, A., Frasson, C., te Kronnie, G. Tags: Genomics Source Type: research

Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior
This study provides new insight into the therapeutic benefit of combining NEDD9 depletion with ROCK inhibition to reduce tumor cell dissemination and discovers a new regulatory role of NEDD9 in the modulation of VAV2-dependent activation of Rac1 and actin polymerization. Mol Cancer Res; 15(6); 670–82. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Jones, B. C., Kelley, L. C., Loskutov, Y. V., Marinak, K. M., Kozyreva, V. K., Smolkin, M. B., Pugacheva, E. N. Tags: Cell Death and Survival Source Type: research