A Systematic Analysis of Negative Growth Control Implicates the DREAM Complex in Cancer Cell Dormancy
This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some cyclin-dependent kinase inhibitors such as p57Kip2, as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested. Many genes essential for EOC spheroid viability are pertinent to the mammalian DREAM repressor complex. Mechanistically, the data demonstrate that DREAM is assembled upon the induction of spheroid formation, which is dependent upon Dyrk1A. Loss of Dyrk1A results i...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: MacDonald, J., Ramos-Valdes, Y., Perampalam, P., Litovchick, L., DiMattia, G. E., Dick, F. A. Tags: Cell Cycle and Senescence Source Type: research

Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis
Metastasis is the consequence of a cancer cell that disperses from the primary tumor, travels throughout the body, and invades and colonizes a distant site. On the basis of Paget's 1889 hypothesis, the majority of modern metastasis research focuses on the properties of the metastatic "seed and soil," but the implications of the primary tumor "soil" have been largely neglected. The rare lethal metastatic "seed" arises as a result of the selective pressures in the primary tumor. Optimal foraging theory describes how cancer cells adopt a mobile foraging strategy to balance predation risk and reso...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: de Groot, A. E., Roy, S., Brown, J. S., Pienta, K. J., Amend, S. R. Tags: Review Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

Retraction: Nek6 Mediates Human Cancer Cell Transformation and Is a Potential Cancer Therapeutic Target
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Tags: Retraction Source Type: research

Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma
This study demonstrates that the nuclear import of JAK1 is essential for the optimal fitness of ABC DLBCL cells, and targeting JAK1 nuclear localization is a potential therapeutic strategy for ABC DLBCL. Mol Cancer Res; 15(3); 348–57. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Zhu, F., Hwang, B., Miyamoto, S., Rui, L. Tags: Signal Transduction Source Type: research

Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors
This study reports the novel findings that HER2 increases PARP1 protein via suppression of the let-7a miRNA, which regulates the PARP1 3'-UTR. Moreover, HER2 status correlates with high PARP1 and low let-7a in breast cancer clinical specimens. Mol Cancer Res; 15(3); 340–7. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Wielgos, M. E., Rajbhandari, R., Cooper, T. S., Wei, S., Nozell, S., Yang, E. S. Tags: Signal Transduction Source Type: research

Functional Activation of Mutant p53 by Platinum Analogues in Cisplatin-Resistant Cells Is Dependent on Phosphorylation
Dysfunctionality of the p53 tumor suppressor is a major cause of therapeutic drug resistance in cancer. Recently, we reported that mutant, but otherwise functional, p53v172F was inactivated in cisplatin-resistant 2780CP/Cl-16 and 2780CP/Cl-24 human ovarian tumor cells by increased recruitment of the inhibitor MDM4. The current study demonstrates that, unlike cisplatin, platinum analogues oxaliplatin and DACH-diacetato-dichloro-Pt(IV) (DAP) strongly stabilize and activate p53v172F in resistant cells, as indicated by prolonged p53 half-life and transactivation of targets p21 (CDKN1A) and MDM2. This increase in MDM2 reduced M...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Xie, X., He, G., Siddik, Z. H. Tags: Oncogenes and Tumor Suppressors Source Type: research

Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations
Therapeutic targeting of the PI3K pathway is an active area of research in multiple cancer types, including breast and endometrial cancers. This pathway is commonly altered in cancer and plays an integral role in numerous vital cellular functions. Mutations in the PIK3CA gene, resulting in a constitutively active form of PI3K, often occur in colorectal cancer, though the population of patients who would benefit from targeting this pathway has yet to be identified. In human colorectal cancers, PIK3CA mutations most commonly occur concomitantly with loss of adenomatous polyposis coli (APC). Here, treatment strategies are inv...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Foley, T. M., Payne, S. N., Pasch, C. A., Yueh, A. E., Van De Hey, D. R., Korkos, D. P., Clipson, L., Maher, M. E., Matkowskyj, K. A., Newton, M. A., Deming, D. A. Tags: Oncogenes and Tumor Suppressors Source Type: research

Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC
Understanding the mechanism of metastatic dissemination is crucial for the rational design of novel therapeutics. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which has been extensively associated with human breast cancer aggressiveness although the underlying mechanisms are still unclear. Here, shRNA-mediated SPARC knockdown greatly reduced primary tumor growth and completely abolished lung colonization of murine 4T1 and LM3 breast malignant cells implanted in syngeneic BALB/c mice. A comprehensive study including global transcriptomic analysis followed by biological validations...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Güttlein, L. N., Benedetti, L. G., Fresno, C., Spallanzani, R. G., Mansilla, S. F., Rotondaro, C., Raffo Iraolagoitia, X. L., Salvatierra, E., Bravo, A. I., Fernandez, E. A., Gottifredi, V., Zwirner, N. W., Llera, A. S., Podhajcer, O. L. Tags: Oncogenes and Tumor Suppressors Source Type: research

LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML
PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo. Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell–like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thu...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Zhou, J., Chan, Z.-L., Bi, C., Lu, X., Chong, P. S. Y., Chooi, J.-Y., Cheong, L.-L., Liu, S.-C., Ching, Y. Q., Zhou, Y., Osato, M., Tan, T. Z., Ng, C. H., Ng, S.-B., Wang, S., Zeng, Q., Chng, W.-J. Tags: Oncogenes and Tumor Suppressors Source Type: research

Pathology-Driven Comprehensive Proteomic Profiling of the Prostate Cancer Tumor Microenvironment
This report undertook a detailed molecular characterization of the tumor microenvironment in prostate cancer to define the proteome in the epithelial and stromal regions from tumor foci of Gleason grades 3 and 4. Tissue regions of interest were isolated from several Gleason 3+3 and Gleason 4+4 tumors using telepathology to leverage specialized pathology expertise to support LCM. Over 2,000 proteins were identified following liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of all regions of interest. Statistical analysis revealed significant differences in protein expression (>100 proteins) between Glea...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Staunton, L., Tonry, C., Lis, R., Espina, V., Liotta, L., Inzitari, R., Bowden, M., Fabre, A., O'Leary, J., Finn, S. P., Loda, M., Pennington, S. R. Tags: Genomics Source Type: research

DNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy
Resistance to cancer chemotherapies leads to deadly consequences, yet current research focuses only on the roles of somatically acquired mutations in this resistance. The mutational status of the germline is also likely to play a role in the way cells respond to chemotherapy. The carrier status for the POLB rs3136797 germline mutation encoding P242R DNA polymerase beta (Pol β) is associated with poor prognosis for lung cancer, specifically in response to treatment with cisplatin. Here, it is revealed that the P242R mutation is sufficient to promote resistance to cisplatin in human cells and in mouse xenografts. Mechan...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Nemec, A. A., Abriola, L., Merkel, J. S., de Stanchina, E., DeVeaux, M., Zelterman, D., Glazer, P. M., Sweasy, J. B. Tags: DNA Damage and Repair Source Type: research

Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade
An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Williams, M. M., Lee, L., Hicks, D. J., Joly, M. M., Elion, D., Rahman, B., McKernan, C., Sanchez, V., Balko, J. M., Stricker, T., Estrada, M. V., Cook, R. S. Tags: Cell Death and Survival Source Type: research

Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma
This study shows that autophagy inhibition enhances sunitinib-mediated cell death in a preclinical model of CCOC. Mol Cancer Res; 15(3); 250–8. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: DeVorkin, L., Hattersley, M., Kim, P., Ries, J., Spowart, J., Anglesio, M. S., Levi, S. M., Huntsman, D. G., Amaravadi, R. K., Winkler, J. D., Tinker, A. V., Lum, J. J. Tags: Cell Death and Survival Source Type: research

Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth
Senescent cells within the tumor microenvironment (TME) adopt a proinflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression, and therapeutic resistance. Here, exposure to palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage–independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-B activation. Based upon these observations, it was hypothesized that the exposure of nontransformed stromal cel...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Guan, X., LaPak, K. M., Hennessey, R. C., Yu, C. Y., Shakya, R., Zhang, J., Burd, C. E. Tags: Cell Cycle and Senescence Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

Astrocyte Elevated Gene-1 Regulates {beta}-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal
This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225–33. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Hu, B., Emdad, L., Kegelman, T. P., Shen, X.-N., Das, S. K., Sarkar, D., Fisher, P. B. Tags: Signal Transduction Source Type: research

MYC Mediates mRNA Cap Methylation of Canonical Wnt/{beta}-Catenin Signaling Transcripts By Recruiting CDK7 and RNA Methyltransferase
MYC is a pleiotropic transcription factor that activates and represses a wide range of target genes and is frequently deregulated in human tumors. While much is known about the role of MYC in transcriptional activation and repression, MYC can also regulate mRNA cap methylation through a mechanism that has remained poorly understood. Here, it is reported that MYC enhances mRNA cap methylation of transcripts globally, specifically increasing mRNA cap methylation of genes involved in Wnt/β-catenin signaling. Elevated mRNA cap methylation of Wnt signaling transcripts in response to MYC leads to augmented translational cap...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Posternak, V., Ung, M. H., Cheng, C., Cole, M. D. Tags: Oncogenes and Tumor Suppressors Source Type: research

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with the 5-year survival rate less than 6%. Previous results indicated that serum levels of CA125 (encoded by MUC16) could be used to predict which groups of pancreatic cancer patients may benefit from surgery. However, the underlying mechanism remains elusive. Herein, using the Cancer Genome Atlas and clinicopathologic data obtained from our center, we demonstrate that high CA125 serum levels and expression levels of MUC16 are predictive of poor prognosis. MUC16 is also validated as a downstream target of KRAS, and their expression strongly correlated with e...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Liang, C., Qin, Y., Zhang, B., Ji, S., Shi, S., Xu, W., Liu, J., Xiang, J., Liang, D., Hu, Q., Ni, Q., Xu, J., Yu, X. Tags: Oncogenes and Tumor Suppressors Source Type: research

Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype
Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration, and survival in many cell types. Here, the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: noninvasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wntliver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quanti...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Ashkavand, Z., O'Flanagan, C., Hennig, M., Du, X., Hursting, S. D., Krupenko, S. A. Tags: Metabolism Source Type: research

High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV
In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR, and in situ hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positiv...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Walline, H. M., Carey, T. E., Goudsmit, C. M., Bellile, E. L., D'Souza, G., Peterson, L. A., McHugh, J. B., Pai, S. I., Lee, J. J., Shin, D. M., Ferris, R. L., on behalf of the HNC SPORE HIV supplement consortium Tags: Genomics Source Type: research

Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis
Lipolysis-stimulated lipoprotein receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. C...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Reaves, D. K., Hoadley, K. A., Fagan-Solis, K. D., Jima, D. D., Bereman, M., Thorpe, L., Hicks, J., McDonald, D., Troester, M. A., Perou, C. M., Fleming, J. M. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

A New Role for ER{alpha}: Silencing via DNA Methylation of Basal, Stem Cell, and EMT Genes
Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α–positive (ERα+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα+ status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα+ cells but derepressed upon exposure to t...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Ariazi, E. A., Taylor, J. C., Black, M. A., Nicolas, E., Slifker, M. J., Azzam, D. J., Boyd, J. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Combined Parthenolide and Balsalazide Have Enhanced Antitumor Efficacy Through Blockade of NF-{kappa}B Activation
This study represents the first evidence that combination therapy with balsalazide and parthenolide could be a new regimen for colorectal cancer treatment. Mol Cancer Res; 15(2); 141–51. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Kim, S.-L., Kim, S. H., Park, Y. R., Liu, Y.-C., Kim, E.-M., Jeong, H.-J., Kim, Y. N., Seo, S. Y., Kim, I. H., Lee, S. O., Lee, S. T., Kim, S.-W. Tags: Cell Death and Survival Source Type: research

The Efflux Transporter ABCG2 Maintains Prostate Stem Cells
This study identifies the mechanism by which the prostate stem cell marker, ABCG2, plays a role in prostate stem cell maintenance and provides a rationale for targeting ABCG2 for differentiation therapy in prostate cancer. Mol Cancer Res; 15(2); 128–40. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Sabnis, N. G., Miller, A., Titus, M. A., Huss, W. J. Tags: Cell Death and Survival Source Type: research

Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation
Deubiquitinases (DUB) are increasingly linked to the regulation of fundamental processes in normal and cancer cells, including DNA replication and repair, programmed cell death, and oncogenes and tumor suppressor signaling. Here, evidence is presented that the deubiquitinase OTUD6B regulates protein synthesis in non–small cell lung cancer (NSCLC) cells, operating downstream from mTORC1. OTUD6B associates with the protein synthesis initiation complex and modifies components of the 48S preinitiation complex. The two main OTUD6B splicing isoforms seem to regulate protein synthesis in opposing fashions: the long OTUD6B-1...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Sobol, A., Askonas, C., Alani, S., Weber, M. J., Ananthanarayanan, V., Osipo, C., Bocchetta, M. Tags: Cell Cycle and Senescence Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

Overcoming EGFR Bypass Signal-Induced Acquired Resistance to ALK Tyrosine Kinase Inhibitors in ALK-Translocated Lung Cancer
This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway–induced acquired resistance to ALK-TKIs. To this end, ceritinib-resistant cells (H3122-CER) were established from the H3122 NSCLC cell line harboring the ALK gene rearrangement via long-term exposure to ceritinib. H3122-CER cells acquired resistance to ceritinib through EGFR bypass pathway activation. Furthermore, H3122 cells that became resistant to ceritinib or alectinib through EGFR pathway activation showed cross-resistance to other ALK-TKIs. Ceritinib and afatinib combination ...
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Miyawaki, M., Yasuda, H., Tani, T., Hamamoto, J., Arai, D., Ishioka, K., Ohgino, K., Nukaga, S., Hirano, T., Kawada, I., Naoki, K., Hayashi, Y., Betsuyaku, T., Soejima, K. Tags: Signal Transduction Source Type: research

Exosomal Annexin II Promotes Angiogenesis and Breast Cancer Metastasis
In this study, mechanistic insight was sought regarding exo-Anx II and its function in angiogenesis and breast cancer metastasis. Multiple in vitro and in vivo techniques were used to study the role of exo-Anx II in angiogenesis. Using atomic force microscopy and Western blotting, exo-Anx II expression was characterized in normal and breast cancer cells. In addition, organ-specific metastatic breast cancer cells and animal models were used to define the role exo-Anx II in breast cancer metastasis. Results revealed that exo-Anx II expression is significantly higher in malignant cells than normal and premetastatic breast can...
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Maji, S., Chaudhary, P., Akopova, I., Nguyen, P. M., Hare, R. J., Gryczynski, I., Vishwanatha, J. K. Tags: Signal Transduction Source Type: research

Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells
This study indicates that ovarian cancer–derived exosomes transfer CD44 to HPMCs, facilitating cancer invasion. Implications: Mechanistic insight from the current study suggests that therapeutic targeting of exosomes may be beneficial in treating ovarian cancer. Mol Cancer Res; 15(1); 78–92. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Nakamura, K., Sawada, K., Kinose, Y., Yoshimura, A., Toda, A., Nakatsuka, E., Hashimoto, K., Mabuchi, S., Morishige, K.-i., Kurachi, H., Lengyel, E., Kimura, T. Tags: Signal Transduction Source Type: research

Src Family Kinases Are Regulated in Multiple Myeloma Cells by Phosphatase of Regenerating Liver-3
In conclusion, PRL-3 protected MM cells against apoptosis by dysregulating both the total levels and the activation levels of specific SFK members that are important for IL6 signal transduction in MM cells. Eventually, this led to increased levels of Mcl-1. Implications: This study suggests PRL-3 and SFKs are key mediators of the IL6-driven signaling events and points to both PRL-3 and SFK members as potential targets for treatment of MM. Mol Cancer Res; 15(1); 69–77. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Abdollahi, P., Vandsemb, E. N., Hjort, M. A., Misund, K., Holien, T., Sponaas, A.-M., Ro, T. B., Slordahl, T. S., Borset, M. Tags: Signal Transduction Source Type: research

Interplay between Cytoplasmic and Nuclear Androgen Receptor Splice Variants Mediates Castration Resistance
This study suggests important consequences for clinical castration resistance due to simultaneous expression of AR-FL and AR-Vs in patient tumors and suggests that dissecting these interactions should help develop effective strategies to disrupt AR-V signaling. Mol Cancer Res; 15(1); 59–68. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Zhan, Y., Zhang, G., Wang, X., Qi, Y., Bai, S., Li, D., Ma, T., Sartor, O., Flemington, E. K., Zhang, H., Lee, P., Dong, Y. Tags: Signal Transduction Source Type: research

AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers
Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance, and metastasis. The mechanistic role of upstream mediators of EMT has not yet been well characterized. Recently, we showed that non–small cell lung cancers (NSCLC) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBC) and head and neck squamous cell carcinomas (HNSCC), and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to c...
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Balaji, K., Vijayaraghavan, S., Diao, L., Tong, P., Fan, Y., Carey, J. P. W., Bui, T. N., Warner, S., Heymach, J. V., Hunt, K. K., Wang, J., Byers, L. A., Keyomarsi, K. Tags: DNA Damage and Repair Source Type: research

Exploitation of Castration-Resistant Prostate Cancer Transcription Factor Dependencies by the Novel BET Inhibitor ABBV-075
Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/superenhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here, the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the androgen receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibito...
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Faivre, E. J., Wilcox, D., Lin, X., Hessler, P., Torrent, M., He, W., Uziel, T., Albert, D. H., McDaniel, K., Kati, W., Shen, Y. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Autophagy Induction Results in Enhanced Anoikis Resistance in Models of Peritoneal Disease
Peritoneal carcinomatosis and peritoneal sarcomatosis is a potential complication of nearly all solid tumors and results in profoundly increased morbidity and mortality. Despite the ubiquity of peritoneal carcinomatosis/peritoneal sarcomatosis, there are no clinically relevant targeted therapies for either its treatment or prevention. To identify potential therapies, we developed in vitro models of peritoneal carcinomatosis/peritoneal sarcomatosis using tumor cell lines and patient-derived spheroids (PDS) that recapitulate anoikis resistance and spheroid proliferation across multiple cancer types. Epithelial- and mesenchym...
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Chen, J. L., David, J., Cook-Spaeth, D., Casey, S., Cohen, D., Selvendiran, K., Bekaii-Saab, T., Hays, J. L. Tags: Cell Death and Survival Source Type: research

ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma is characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich stroma associated with this disease has been implicated as a barrier to drug penetration, although stromal depletion strategies have had mixed clinical success. It remains less clear how interactions with ECM, acting as a biophysical regulator of phenotype, not only a barrier to drug perfusion, regulate susceptibilities and resistance to specific therapies. In this context, an integrative approach is used to evaluate invasive b...
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Cramer, G. M., Jones, D. P., El-Hamidi, H., Celli, J. P. Tags: Cell Death and Survival Source Type: research

Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes
Carcinoma-associated fibroblasts (CAF) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumor progression. However, evidence of both cancer-promoting and -restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared with nonsenescent control CAFs using in vitro Transwell invasion models and in vivo xenograft mouse models. Screening by gene expression microarray and cytokine ELISA assays revealed IL8 to be upregulated in senescent CAFs. Exper...
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Authors: Wang, T., Notta, F., Navab, R., Joseph, J., Ibrahimov, E., Xu, J., Zhu, C.-Q., Borgida, A., Gallinger, S., Tsao, M.-S. Tags: Cell Cycle and Senescence Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 2, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

Acknowledgment to Reviewers
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Tags: Acknowledgment to Reviewers Source Type: research

The Cytoskeletal Adapter Protein Spinophilin Regulates Invadopodia Dynamics and Tumor Cell Invasion in Glioblastoma
Glioblastoma is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive glioblastoma cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin αvβ8 and its intracellular binding partner, Spinophilin (Spn), which regulates glioblastoma cell...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Cheerathodi, M., Avci, N. G., Guerrero, P. A., Tang, L. K., Popp, J., Morales, J. E., Chen, Z., Carnero, A., Lang, F. F., Ballif, B. A., Rivera, G. M., McCarty, J. H. Tags: Signal Transduction Source Type: research

MUC1-C Represses the Crumbs Complex Polarity Factor CRB3 and Downregulates the Hippo Pathway
Apical–basal polarity and epithelial integrity are maintained in part by the Crumbs (CRB) complex. The C--terminal subunit of MUC1 (MUC1-C) is a transmembrane protein that is expressed at the apical border of normal epithelial cells and aberrantly at high levels over the entire surface of their transformed counterparts. However, it is not known whether MUC1-C contributes to this loss of polarity that is characteristic of carcinoma cells. Here it is demonstrated that MUC1-C downregulates expression of the Crumbs complex CRB3 protein in triple-negative breast cancer (TNBC) cells. MUC1-C associates with ZEB1 on the CRB3...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Alam, M., Bouillez, A., Tagde, A., Ahmad, R., Rajabi, H., Maeda, T., Hiraki, M., Suzuki, Y., Kufe, D. Tags: Oncogenes and Tumor Suppressors Source Type: research

Adipose-Induced Retroperitoneal Soft Tissue Sarcoma Tumorigenesis: A Potential Crosstalk between Sarcoma and Fat Cells
The objective of the current study was to evaluate potential paracrine effects of visceral fat on RSTS. A xenograft model was used to evaluate in vivo effects of human visceral fat on STS growth. Tissue explants were prepared from visceral fat, and their conditioned medium (CM) was utilized for various in vitro experiments designed to evaluate growth, survival, migration, and invasion of STS and endothelial cells. Visceral fat–secreted protumorigenic factors were identified by mass spectrometry. The in vivo experiments demonstrated a significant increase in STS tumor growth rate when SK-LMS-1 leiomyosarcoma cells wer...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Loewenstein, S., Lubezky, N., Nizri, E., Zemel, M., Levin, Y., Savidor, A., Sher, O., Klausner, J. M., Lahat, G. Tags: Oncogenes and Tumor Suppressors Source Type: research

Heparanase Promotes Glioma Progression and Is Inversely Correlated with Patient Survival
In conclusion, these data provide proof-of-concept for anti-HPSE treatment of malignant glioma, as well as novel insights for the development of HPSE as a therapeutic target. Implications: This study aims to target both the malignant brain tumor cells per se and their microenvironment by changing the level of an enzyme, HPSE, that breaks down modified sugar chains on cell surfaces and in the extracellular space. Mol Cancer Res; 14(12); 1243–53. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Kundu, S., Xiong, A., Spyrou, A., Wicher, G., Marinescu, V. D., Edqvist, P.-H. D., Zhang, L., Essand, M., Dimberg, A., Smits, A., Ilan, N., Vlodavsky, I., Li, J.-P., Forsberg-Nilsson, K. Tags: Oncogenes and Tumor Suppressors Source Type: research

Increased Expression of System xc- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance
Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system xc–, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc– in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc– with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had ...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Polewski, M. D., Reveron-Thornton, R. F., Cherryholmes, G. A., Marinov, G. K., Cassady, K., Aboody, K. S. Tags: Metabolism Source Type: research

Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors
Laterally spreading tumors (LST) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer, depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancers offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome, and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large, benign color...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Hesson, L. B., Ng, B., Zarzour, P., Srivastava, S., Kwok, C.-T., Packham, D., Nunez, A. C., Beck, D., Ryan, R., Dower, A., Ford, C. E., Pimanda, J. E., Sloane, M. A., Hawkins, N. J., Bourke, M. J., Wong, J. W. H., Ward, R. L. Tags: Genomics Source Type: research

MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling
This study describes a potential therapeutic strategy for a subset of colon cancers that are dependent on oncogenic KRAS signaling pathways, which are currently difficult to block with selective agents. Mol Cancer Res; 14(12); 1204–16. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: McNew, K. L., Whipple, W. J., Mehta, A. K., Grant, T. J., Ray, L., Kenny, C., Singh, A. Tags: Cell Death and Survival Source Type: research

Olaparib, Monotherapy or with Ionizing Radiation, Exacerbates DNA Damage in Normal Tissues: Insights from a New p21 Reporter Mouse
Many drugs targeting the DNA damage response are being developed as anticancer therapies, either as single agents or in combination with ionizing radiation (IR) or other cytotoxic agents. Numerous clinical trials in this area are either in progress or planned. However, concerns remain about the potential of such treatments to increase toxicity to normal tissues. In order to address this issue, a novel reporter mouse line was created through the simultaneous incorporation of multiple reporters, β-galactosidase, and firefly luciferase, into the DNA damage–inducible p21 (CDKN1A) locus. The data demonstrate that in ...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: McMahon, M., Frangova, T. G., Henderson, C. J., Wolf, C. R. Tags: DNA Damage and Repair Source Type: research

AMPK{alpha}2 Regulates Bladder Cancer Growth through SKP2-Mediated Degradation of p27
AMP-activated protein kinase (AMPK) is the central metabolic regulator of the cell and controls energy consumption based upon nutrient availability. Due to its role in energy regulation, AMPK has been implicated as a barrier for cancer progression and is suppressed in multiple cancers. To examine whether AMPK regulates bladder cancer cell growth, HTB2 and HT1376 bladder cells were treated with an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). AICAR treatment reduced proliferation and induced the expression of p27Kip1 (CDKN1B), which was mediated through an mTOR-dependent mechanism. Interestingly, AM...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Kopsiaftis, S., Sullivan, K. L., Garg, I., Taylor, J. A., Claffey, K. P. Tags: Cell Cycle and Senescence Source Type: research

Synthetic Lethality in PTEN-Mutant Prostate Cancer Is Induced by Combinatorial PI3K/Akt and BCL-XL Inhibition
This study defines a synthetic lethal therapeutic combination with significant translational potential. Overview: Synthetic lethality in PTEN-mutant prostate cancer cells with combined PI3K/Akt and BCL-XL inhibition. PTEN-mutant prostate cancer cells expressing ITGA5 bind to fibronectin in the putative bone marrow niche and transduce survival signals to BCL-XL. Additional PTEN-regulated signals independent of the PI3K/Akt pathway likely feed into the BCL-XL–regulated survival program to explain synthetic lethality observed with the combination. Visual Overview: http://mcr.aacrjournals.org/content/early/2016/12/02/154...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Ren, W., Joshi, R., Mathew, P. Tags: Rapid Impact Source Type: research

A New Chromatin-Cytoskeleton Link in Cancer
The set domain containing 2 (SETD2) histone methyltransferase, located at 3p2, specifically trimethylates lysine 36 of histone H3 (H3K36me3). H3K36me3 is an active mark involved in transcriptional elongation and RNA processing and a key regulator of DNA repair. In fact, SETD2 is the only methyltransferase that "writes" the H3K36me3 mark. Recent results from Park and colleagues have found a new role for SETD2 in the methylation of K40 of α-tubulin. Loss of SETD2 abolishes methylation of K40 of α-tubulin and results in a dysfunctional mitotic spindle and abnormalities in cytokinesis. Thus, SETD2 links c...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Giaccia, A. J. Tags: Perspective Source Type: research