High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity
This study characterizes the relations between diet and metabolic conditions on risk for a common cancer and identifies complement activation as a novel target for cancer prevention. Mol Cancer Res; 14(10); 953–65. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Doerner, S. K., Reis, E. S., Leung, E. S., Ko, J. S., Heaney, J. D., Berger, N. A., Lambris, J. D., Nadeau, J. H. Tags: Preclinical Intervention Metabolism Source Type: research

Genomic Integration of High-Risk HPV Alters Gene Expression in Oropharyngeal Squamous Cell Carcinoma
In this study, viral factors were examined for possible clues to differences in tumor behavior. Oropharynx tumors that responded well to therapy were compared with those that persisted and recurred. Viral oncogene alternate transcripts were assessed, and cellular sites of viral integration were mapped and sequenced. Effects of integration on gene expression were assessed by transcript analysis at the integration sites. All of the tumors demonstrated active viral oncogenesis, indicated by expression of HPV E6 and E7 oncogenes and alternate E6 splicing. In the responsive tumors, HPV integration occurred exclusively in interg...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Walline, H. M., Komarck, C. M., McHugh, J. B., Bellile, E. L., Brenner, J. C., Prince, M. E., McKean, E. L., Chepeha, D. B., Wolf, G. T., Worden, F. P., Bradford, C. R., Carey, T. E. Tags: Genomics Source Type: research

Augmented HR Repair Mediates Acquired Temozolomide Resistance in Glioblastoma
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults and is universally fatal. The DNA alkylating agent temozolomide is part of the standard-of-care for GBM. However, these tumors eventually develop therapy-driven resistance and inevitably recur. While loss of mismatch repair (MMR) and re-expression of MGMT have been shown to underlie chemoresistance in a fraction of GBMs, resistance mechanisms operating in the remaining GBMs are not well understood. To better understand the molecular basis for therapy-driven temozolomide resistance, mice bearing orthotopic GBM xenografts were subjected to pro...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Gil del Alcazar, C. R., Todorova, P. K., Habib, A. A., Mukherjee, B., Burma, S. Tags: DNA Damage and Repair Source Type: research

Amplification of TLK2 Induces Genomic Instability via Impairing the G2-M Checkpoint
In this study, it was discovered that TLK2 amplification and overexpression mechanistically impair Chk1/2-induced DNA damage checkpoint signaling, leading to a G2–M checkpoint defect, delayed DNA repair process, and increased CIN. In addition, TLK2 overexpression modestly sensitizes breast cancer cells to DNA-damaging agents, such as irradiation or doxorubicin. To our knowledge, this is the first report linking TLK2 function to CIN, in contrast to the function of its paralog TLK1 as a guardian of genome stability. This finding yields new insight into the deregulated DNA damage pathway and increased genomic instabilit...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Kim, J.-A., Anurag, M., Veeraraghavan, J., Schiff, R., Li, K., Wang, X.-S. Tags: DNA Damage and Repair Source Type: research

Bone Marrow Microenvironment Niche Regulates miR-221/222 in Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) has many features in common with normal B-cell progenitors, including their ability to respond to diverse signals from the bone marrow microenvironment (BMM) resulting in regulation of cell-cycle progression and survival. Bone marrow–derived cues influence many elements of both steady state hematopoiesis and hematopoietic tumor cell phenotypes through modulation of gene expression. miRNAs are one regulatory class of small noncoding RNAs that have been shown to be increasingly important in diverse settings of malignancy. In the current study, miRNA profiles were globally altered in A...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Moses, B. S., Evans, R., Slone, W. L., Piktel, D., Martinez, I., Craig, M. D., Gibson, L. F. Tags: Cell Death and Survival Source Type: research

Cell-free DNA (cfDNA): Clinical Significance and Utility in Cancer Shaped By Emerging Technologies
Precision oncology is predicated upon the ability to detect specific actionable genomic alterations and to monitor their adaptive evolution during treatment to counter resistance. Because of spatial and temporal heterogeneity and comorbidities associated with obtaining tumor tissues, especially in the case of metastatic disease, traditional methods for tumor sampling are impractical for this application. Known to be present in the blood of cancer patients for decades, cell-free DNA (cfDNA) is beginning to inform on tumor genetics, tumor burden, and mechanisms of progression and drug resistance. This substrate is amenable f...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Volik, S., Alcaide, M., Morin, R. D., Collins, C. Tags: Cellular Pathobiology Review Source Type: research

There and Back Again: The Middle Earth of DNA Repair
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Knudsen, K. E. Tags: Editorial Editorials Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Tags: Editorial Highlights Source Type: research

Selumetinib Phosphoproteomics in Lung Cancer
This study highlights the unique adaptive changes in MAPK scaffolding proteins (KSR-1, GEF-H1) and in RTK signaling, leading to enhanced PI3K/AKT signaling when the MAPK pathway is inhibited. Mol Cancer Res; 14(10); 1019–29. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Kim, J.-Y., Welsh, E. A., Fang, B., Bai, Y., Kinose, F., Eschrich, S. A., Koomen, J. M., Haura, E. B. Tags: Signal Transduction Source Type: research

ERK Regulates PREX1-RAC1 in Human Melanoma
This study identifies an ERK-dependent mechanism that drives PREX1 upregulation and subsequent RAC1-dependent invasion in BRAF- and NRAS-mutant melanoma. Mol Cancer Res; 14(10); 1009–18. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Ryan, M. B., Finn, A. J., Pedone, K. H., Thomas, N. E., Der, C. J., Cox, A. D. Tags: Signal Transduction Source Type: research

HMGN2 Deacetylation Regulates Stat5a-mediated Transcription
Stat5a is a transcription factor utilized by several cytokine/hormone receptor signaling pathways that promotes transcription of genes associated with proliferation, differentiation, and survival of cancer cells. However, there are currently no clinically approved therapies that directly target Stat5a, despite ample evidence that it contributes to breast cancer pathogenesis. Here, deacetylation of the Stat5a coactivator and chromatin-remodeling protein HMGN2 on lysine residue K2 by HDAC6 promotes Stat5a-mediated transcription and breast cancer growth. HDAC6 inhibition both in vitro and in vivo enhances HMGN2 acetylation wi...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Medler, T. R., Craig, J. M., Fiorillo, A. A., Feeney, Y. B., Harrell, J. C., Clevenger, C. V. Tags: Signal Transduction Source Type: research

MNK Inhibition in Glioma Stem Cells
Glioblastoma multiforme remains the deadliest malignant brain tumor, with glioma stem cells (GSC) contributing to treatment resistance and tumor recurrence. We have identified MAPK-interacting kinases (MNK) as potential targets for the GSC population in glioblastoma multiforme. Isoform-level subtyping using The Cancer Genome Atlas revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal glioblastoma multiforme as compared with other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44, and coexpression of MKNK1 and CD44 predicts po...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Bell, J. B., Eckerdt, F. D., Alley, K., Magnusson, L. P., Hussain, H., Bi, Y., Arslan, A. D., Clymer, J., Alvarez, A. A., Goldman, S., Cheng, S.-Y., Nakano, I., Horbinski, C., Davuluri, R. V., James, C. D., Platanias, L. C. Tags: Signal Transduction Source Type: research

Mutant IDH1-Driven {#x201C}Hit and Run{#x201D} Gliomagenesis
Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. Although mutant IDH1 expression is thought to drive the gliomagenesis process, the extent to which it remains a viable therapeutic target remains unknown. To address thi...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Johannessen, T.-C. A., Mukherjee, J., Viswanath, P., Ohba, S., Ronen, S. M., Bjerkvig, R., Pieper, R. O. Tags: Oncogenes and Tumor Suppressors Source Type: research

BCO2 Inhibits NF-{kappa}B Signaling in Prostate Cancer
This study investigated expression and functional roles of BCO2 in human prostate cancer. Expression of the bco2 gene is dramatically decreased in prostate cancer tissue and in a range of prostate cancer cell lines as compared with nonneoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in prostate cancer cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and reduced cell proliferation in androgen-sensitive cell lines, but lycopene neither altered bco2 expression nor c...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Gong, X., Marisiddaiah, R., Zaripheh, S., Wiener, D., Rubin, L. P. Tags: Oncogenes and Tumor Suppressors Source Type: research

Complement Activation and Intestinal Tumorigenesis
This study characterizes the relations between diet and metabolic conditions on risk for a common cancer and identifies complement activation as a novel target for cancer prevention. Mol Cancer Res; 14(10); 953–65. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Doerner, S. K., Reis, E. S., Leung, E. S., Ko, J. S., Heaney, J. D., Berger, N. A., Lambris, J. D., Nadeau, J. H. Tags: Metabolism Source Type: research

HPV Integration in Oropharynx Tumors and Recurrence
In this study, viral factors were examined for possible clues to differences in tumor behavior. Oropharynx tumors that responded well to therapy were compared with those that persisted and recurred. Viral oncogene alternate transcripts were assessed, and cellular sites of viral integration were mapped and sequenced. Effects of integration on gene expression were assessed by transcript analysis at the integration sites. All of the tumors demonstrated active viral oncogenesis, indicated by expression of HPV E6 and E7 oncogenes and alternate E6 splicing. In the responsive tumors, HPV integration occurred exclusively in interg...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Walline, H. M., Komarck, C. M., McHugh, J. B., Bellile, E. L., Brenner, J. C., Prince, M. E., McKean, E. L., Chepeha, D. B., Wolf, G. T., Worden, F. P., Bradford, C. R., Carey, T. E. Tags: Genomics Source Type: research

Augmented HR Underlies Acquired Temozolomide Resistance
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults and is universally fatal. The DNA alkylating agent temozolomide is part of the standard-of-care for GBM. However, these tumors eventually develop therapy-driven resistance and inevitably recur. While loss of mismatch repair (MMR) and re-expression of MGMT have been shown to underlie chemoresistance in a fraction of GBMs, resistance mechanisms operating in the remaining GBMs are not well understood. To better understand the molecular basis for therapy-driven temozolomide resistance, mice bearing orthotopic GBM xenografts were subjected to pro...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Gil del Alcazar, C. R., Todorova, P. K., Habib, A. A., Mukherjee, B., Burma, S. Tags: DNA Damage and Repair Source Type: research

Role of TLK2 in Breast Cancer Genomic Instability
In this study, it was discovered that TLK2 amplification and overexpression mechanistically impair Chk1/2-induced DNA damage checkpoint signaling, leading to a G2–M checkpoint defect, delayed DNA repair process, and increased CIN. In addition, TLK2 overexpression modestly sensitizes breast cancer cells to DNA-damaging agents, such as irradiation or doxorubicin. To our knowledge, this is the first report linking TLK2 function to CIN, in contrast to the function of its paralog TLK1 as a guardian of genome stability. This finding yields new insight into the deregulated DNA damage pathway and increased genomic instabilit...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Kim, J.-A., Anurag, M., Veeraraghavan, J., Schiff, R., Li, K., Wang, X.-S. Tags: DNA Damage and Repair Source Type: research

Microenvironment Regulation of miR-221/222 in ALL
Acute lymphoblastic leukemia (ALL) has many features in common with normal B-cell progenitors, including their ability to respond to diverse signals from the bone marrow microenvironment (BMM) resulting in regulation of cell-cycle progression and survival. Bone marrow–derived cues influence many elements of both steady state hematopoiesis and hematopoietic tumor cell phenotypes through modulation of gene expression. miRNAs are one regulatory class of small noncoding RNAs that have been shown to be increasingly important in diverse settings of malignancy. In the current study, miRNA profiles were globally altered in A...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Moses, B. S., Evans, R., Slone, W. L., Piktel, D., Martinez, I., Craig, M. D., Gibson, L. F. Tags: Cell Death and Survival Source Type: research

Emerging Technologies for Circulating DNA Studies
Precision oncology is predicated upon the ability to detect specific actionable genomic alterations and to monitor their adaptive evolution during treatment to counter resistance. Because of spatial and temporal heterogeneity and comorbidities associated with obtaining tumor tissues, especially in the case of metastatic disease, traditional methods for tumor sampling are impractical for this application. Known to be present in the blood of cancer patients for decades, cell-free DNA (cfDNA) is beginning to inform on tumor genetics, tumor burden, and mechanisms of progression and drug resistance. This substrate is amenable f...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Volik, S., Alcaide, M., Morin, R. D., Collins, C. Tags: Review Source Type: research

Editorial
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Knudsen, K. E. Tags: Editorials Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity
Oral squamous cell carcinoma (OSCC) is a cancer subtype that lacks validated prognostic and therapeutic biomarkers, and human papillomavirus status has not proven beneficial in predicting patient outcomes. A gene expression pathway analysis was conducted using OSCC patient specimens to identify molecular targets that may improve management of this disease. RNA was isolated from 19 OSCCs treated surgically at the University of Alabama at Birmingham (UAB; Birmingham, AL) and evaluated using the NanoString nCounter system. Results were confirmed using the oral cavity subdivision of the Head and Neck Squamous Cell Carcinoma Ca...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Weaver, A. N., Burch, M. B., Cooper, T. S., Della Manna, D. L., Wei, S., Ojesina, A. I., Rosenthal, E. L., Yang, E. S. Tags: Signal Transduction Source Type: research

FAK Expression, Not Kinase Activity, Is a Key Mediator of Thyroid Tumorigenesis and Protumorigenic Processes
This study demonstrates that FAK expression, but not kinase activity alone, predominantly mediates thyroid tumor growth and metastasis, indicating that targeting the scaffolding function(s) of FAK may be an important therapeutic strategy for advanced thyroid cancer, as well as other FAK-dependent tumors. Mol Cancer Res; 14(9); 869–82. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Kessler, B. E., Sharma, V., Zhou, Q., Jing, X., Pike, L. A., Kerege, A. A., Sams, S. B., Schweppe, R. E. Tags: Signal Transduction Source Type: research

Novel Bispecific Domain Antibody to LRP6 Inhibits Wnt and R-spondin Ligand-Induced Wnt Signaling and Tumor Growth
This article demonstrates the inhibition of a key oncogenic receptor, intractable to mAb inhibition due to multiple independent ligand interaction sites, using an innovative dAb approach. Mol Cancer Res; 14(9); 859–68. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Jackson, H., Granger, D., Jones, G., Anderson, L., Friel, S., Rycroft, D., Fieles, W., Tunstead, J., Steward, M., Wattam, T., Walker, A., Griggs, J., Al-Hajj, M., Shelton, C. Tags: Signal Transduction Source Type: research

SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer
The oncofetal protein sine oculis-related homeobox 1 (SIX1) is a developmental transcription factor associated with carcinogenesis in several human cancer types but has not been investigated in human endometrial cancer. In a model of hormonal carcinogenesis, mice neonatally exposed to the soy phytoestrogen genistein (GEN) or the synthetic estrogen diethylstilbestrol (DES) develop endometrial cancer as adults. Previously, we demonstrated that SIX1 becomes aberrantly expressed in the uteri of these mice. Here, we used this mouse model to investigate the role of SIX1 expression in endometrial carcinoma development and used hu...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Suen, A. A., Jefferson, W. N., Wood, C. E., Padilla-Banks, E., Bae-Jump, V. L., Williams, C. J. Tags: Oncogenes and Tumor Suppressors Source Type: research

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis
In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer. Key results were validated in an independent collection of tumors with matched adjacent mucosa and by mining of a publicly available expression data set. Protein expression was analyzed by immunoblotting for cell lines or IHC for patient specimens that further included 24 cases of adenocarcinoma with adjacent dysplasia and 11 cases o...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Cantarino, N., Musulen, E., Valero, V., Peinado, M. A., Perucho, M., Moreno, V., Forcales, S.-V., Douet, J., Buschbeck, M. Tags: Oncogenes and Tumor Suppressors Source Type: research

Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma
In this study, we sought to determine the role of Gas1 in tumorigenesis and metastasis, and elucidate the possible mechanism. First, Gas1 was determined as a negative regulator of oncogenesis and metastasis in colorectal cancer. Mechanistically, Gas1 negatively regulated the aerobic glycolysis, a process that contributed to tumor progression and metastasis by providing energy source and building blocks for macromolecule synthesis. To further consolidate the role of Gas1 in glycolysis, the impact of Gas1 in the transcription of key glycolytic enzymes for glucose utilization was examined. As expected, GLUT4, HK2, and LDHB ex...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Li, Q., Qin, Y., Wei, P., Lian, P., Li, Y., Xu, Y., Li, X., Li, D., Cai, S. Tags: Metabolism Source Type: research

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial-Mesenchymal Transition-like Process and 22q Loss
Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presen...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Stacchiotti, S., Astolfi, A., Gronchi, A., Fontana, A., Pantaleo, M. A., Negri, T., Brenca, M., Tazzari, M., Urbini, M., Indio, V., Colombo, C., Radaelli, S., Brich, S., Dei Tos, A. P., Casali, P. G., Castelli, C., Dagrada, G. P., Pilotti, S., Maestro, R. Tags: Genomics Source Type: research

A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes
This study reveals a functional minimal methylation profile in oral tongue tumors with associated risk habits, clinical, and epidemiologic outcomes. In addition, NR4A3 downregulation and correlation with patient survival suggests a potential target for therapeutic intervention in oral tongue tumors. Data from the current study are deposited in the NCBI Geo database (accession number GSE75540). Mol Cancer Res; 14(9); 805–19. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Krishnan, N. M., Dhas, K., Nair, J., Palve, V., Bagwan, J., Siddappa, G., Suresh, A., Kekatpure, V. D., Kuriakose, M. A., Panda, B. Tags: Genomics Source Type: research

Distinct Transcriptional Changes and Epithelial-Stromal Interactions Are Altered in Early-Stage Colon Cancer Development
Although the progression of mutated colonic cells is dependent upon interactions between the initiated epithelium and surrounding stroma, the nature of these interactions is poorly understood. Here, the development of an ultrasensitive laser capture microdissection (LCM)/RNA-seq approach for studying the epithelial and stromal compartments of aberrant crypt foci (ACF) is described. ACF are the earliest identifiable preneoplastic lesion found within the human colon and are detected using high-definition endoscopy with contrast dye spray. The current analysis focused on the epithelium of ACF with somatic mutations to either ...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Mo, A., Jackson, S., Varma, K., Carpino, A., Giardina, C., Devers, T. J., Rosenberg, D. W. Tags: Genomics Source Type: research

DNA Methylome Analyses Implicate Fallopian Tube Epithelia as the Origin for High-Grade Serous Ovarian Cancer
High-grade serous ovarian cancer (HGSC) is the most common and lethal form of epithelial ovarian cancer (EOC). Two distinct tissues have been suggested as the tissue of origin: ovarian surface epithelia (OSE) and fallopian tube epithelia (FTE). We hypothesized that the DNA methylome of HGSC should more closely resemble the methylome of its tissue of origin. To this end, we profiled HGSC (n = 10), and patient-matched OSE and FTE (n = 5) primary fresh-frozen tissues, and analyzed the DNA methylome using Illumina 450K arrays (n = 20) and Agilent Sure Select methyl-seq (n = 7). Methylomes were compared using statistical analys...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Klinkebiel, D., Zhang, W., Akers, S. N., Odunsi, K., Karpf, A. R. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Cholesterol Sulfonation Enzyme, SULT2B1b, Modulates AR and Cell Growth Properties in Prostate Cancer
Cholesterol accumulates in prostate lesions and has been linked to prostate cancer incidence and progression. However, how accumulated cholesterol contributes to prostate cancer development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared with normal regions of the same tissue sample. Given the enhanced accumulation of CS in these lesions, it was hypothesized that SULT2B1b-mediated production of CS provides...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Vickman, R. E., Crist, S. A., Kerian, K., Eberlin, L., Cooks, R. G., Burcham, G. N., Buhman, K. K., Hu, C.-D., Mesecar, A. D., Cheng, L., Ratliff, T. L. Tags: Cell Death and Survival Source Type: research

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma
In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Fatkhutdinov, N., Sproesser, K., Krepler, C., Liu, Q., Brafford, P. A., Herlyn, M., Aird, K. M., Zhang, R. Tags: Cell Cycle and Senescence Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

Notch Activation Is Associated with Mortality in OSCC
Oral squamous cell carcinoma (OSCC) is a cancer subtype that lacks validated prognostic and therapeutic biomarkers, and human papillomavirus status has not proven beneficial in predicting patient outcomes. A gene expression pathway analysis was conducted using OSCC patient specimens to identify molecular targets that may improve management of this disease. RNA was isolated from 19 OSCCs treated surgically at the University of Alabama at Birmingham (UAB; Birmingham, AL) and evaluated using the NanoString nCounter system. Results were confirmed using the oral cavity subdivision of the Head and Neck Squamous Cell Carcinoma Ca...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Weaver, A. N., Burch, M. B., Cooper, T. S., Della Manna, D. L., Wei, S., Ojesina, A. I., Rosenthal, E. L., Yang, E. S. Tags: Signal Transduction Source Type: research

The Role of Focal Adhesion Kinase (FAK) in Thyroid Cancer
This study demonstrates that FAK expression, but not kinase activity alone, predominantly mediates thyroid tumor growth and metastasis, indicating that targeting the scaffolding function(s) of FAK may be an important therapeutic strategy for advanced thyroid cancer, as well as other FAK-dependent tumors. Mol Cancer Res; 14(9); 869–82. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Kessler, B. E., Sharma, V., Zhou, Q., Jing, X., Pike, L. A., Kerege, A. A., Sams, S. B., Schweppe, R. E. Tags: Signal Transduction Source Type: research

Wnt Pathway Inhibition by an LRP6 Bispecific dAb
This article demonstrates the inhibition of a key oncogenic receptor, intractable to mAb inhibition due to multiple independent ligand interaction sites, using an innovative dAb approach. Mol Cancer Res; 14(9); 859–68. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Jackson, H., Granger, D., Jones, G., Anderson, L., Friel, S., Rycroft, D., Fieles, W., Tunstead, J., Steward, M., Wattam, T., Walker, A., Griggs, J., Al-Hajj, M., Shelton, C. Tags: Signal Transduction Source Type: research

SIX1 and Endometrial Cancer
The oncofetal protein sine oculis-related homeobox 1 (SIX1) is a developmental transcription factor associated with carcinogenesis in several human cancer types but has not been investigated in human endometrial cancer. In a model of hormonal carcinogenesis, mice neonatally exposed to the soy phytoestrogen genistein (GEN) or the synthetic estrogen diethylstilbestrol (DES) develop endometrial cancer as adults. Previously, we demonstrated that SIX1 becomes aberrantly expressed in the uteri of these mice. Here, we used this mouse model to investigate the role of SIX1 expression in endometrial carcinoma development and used hu...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Suen, A. A., Jefferson, W. N., Wood, C. E., Padilla-Banks, E., Bae-Jump, V. L., Williams, C. J. Tags: Oncogenes and Tumor Suppressors Source Type: research

PADI2 Is Lost in Colorectal Cancer
In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer. Key results were validated in an independent collection of tumors with matched adjacent mucosa and by mining of a publicly available expression data set. Protein expression was analyzed by immunoblotting for cell lines or IHC for patient specimens that further included 24 cases of adenocarcinoma with adjacent dysplasia and 11 cases o...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Cantarino, N., Musulen, E., Valero, V., Peinado, M. A., Perucho, M., Moreno, V., Forcales, S.-V., Douet, J., Buschbeck, M. Tags: Oncogenes and Tumor Suppressors Source Type: research

Gas1 Expression in Colorectal Cancer
In this study, we sought to determine the role of Gas1 in tumorigenesis and metastasis, and elucidate the possible mechanism. First, Gas1 was determined as a negative regulator of oncogenesis and metastasis in colorectal cancer. Mechanistically, Gas1 negatively regulated the aerobic glycolysis, a process that contributed to tumor progression and metastasis by providing energy source and building blocks for macromolecule synthesis. To further consolidate the role of Gas1 in glycolysis, the impact of Gas1 in the transcription of key glycolytic enzymes for glucose utilization was examined. As expected, GLUT4, HK2, and LDHB ex...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Li, Q., Qin, Y., Wei, P., Lian, P., Li, Y., Xu, Y., Li, X., Li, D., Cai, S. Tags: Metabolism Source Type: research

Dermatofibrosarcoma Protuberans and Fibrosarcomatous DFSP
Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presen...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Stacchiotti, S., Astolfi, A., Gronchi, A., Fontana, A., Pantaleo, M. A., Negri, T., Brenca, M., Tazzari, M., Urbini, M., Indio, V., Colombo, C., Radaelli, S., Brich, S., Dei Tos, A. P., Casali, P. G., Castelli, C., Dagrada, G. P., Pilotti, S., Maestro, R. Tags: Genomics Source Type: research

DNA Methylation in Oral Tongue Tumors
This study reveals a functional minimal methylation profile in oral tongue tumors with associated risk habits, clinical, and epidemiologic outcomes. In addition, NR4A3 downregulation and correlation with patient survival suggests a potential target for therapeutic intervention in oral tongue tumors. Data from the current study are deposited in the NCBI Geo database (accession number GSE75540). Mol Cancer Res; 14(9); 805–19. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Krishnan, N. M., Dhas, K., Nair, J., Palve, V., Bagwan, J., Siddappa, G., Suresh, A., Kekatpure, V. D., Kuriakose, M. A., Panda, B. Tags: Genomics Source Type: research

Epithelia-Stroma Cross-talk in Right Colon ACF
Although the progression of mutated colonic cells is dependent upon interactions between the initiated epithelium and surrounding stroma, the nature of these interactions is poorly understood. Here, the development of an ultrasensitive laser capture microdissection (LCM)/RNA-seq approach for studying the epithelial and stromal compartments of aberrant crypt foci (ACF) is described. ACF are the earliest identifiable preneoplastic lesion found within the human colon and are detected using high-definition endoscopy with contrast dye spray. The current analysis focused on the epithelium of ACF with somatic mutations to either ...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Mo, A., Jackson, S., Varma, K., Carpino, A., Giardina, C., Devers, T. J., Rosenberg, D. W. Tags: Genomics Source Type: research

DNA Methylome of Ovarian Cancer and Tissues of Origin
High-grade serous ovarian cancer (HGSC) is the most common and lethal form of epithelial ovarian cancer (EOC). Two distinct tissues have been suggested as the tissue of origin: ovarian surface epithelia (OSE) and fallopian tube epithelia (FTE). We hypothesized that the DNA methylome of HGSC should more closely resemble the methylome of its tissue of origin. To this end, we profiled HGSC (n = 10), and patient-matched OSE and FTE (n = 5) primary fresh-frozen tissues, and analyzed the DNA methylome using Illumina 450K arrays (n = 20) and Agilent Sure Select methyl-seq (n = 7). Methylomes were compared using statistical analys...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Klinkebiel, D., Zhang, W., Akers, S. N., Odunsi, K., Karpf, A. R. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

SULT2B1b Influences AR Activity and Cell Growth
Cholesterol accumulates in prostate lesions and has been linked to prostate cancer incidence and progression. However, how accumulated cholesterol contributes to prostate cancer development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared with normal regions of the same tissue sample. Given the enhanced accumulation of CS in these lesions, it was hypothesized that SULT2B1b-mediated production of CS provides...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Vickman, R. E., Crist, S. A., Kerian, K., Eberlin, L., Cooks, R. G., Burcham, G. N., Buhman, K. K., Hu, C.-D., Mesecar, A. D., Cheng, L., Ratliff, T. L. Tags: Cell Death and Survival Source Type: research

Combinatorial Inhibition of RRM2 and BRAF for Melanoma
In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression...
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Authors: Fatkhutdinov, N., Sproesser, K., Krepler, C., Liu, Q., Brafford, P. A., Herlyn, M., Aird, K. M., Zhang, R. Tags: Cell Cycle and Senescence Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - September 12, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

JNK1 Inhibition Attenuates Hypoxia-Induced Autophagy and Sensitizes to Chemotherapy
Inhibition of hypoxia-induced stress signaling through JNK potentiates the effects of oxaliplatin. The JNK pathway plays a role in both autophagy and apoptosis; therefore, it was determined how much of the effect of JNK inhibition on oxaliplatin sensitivity is dependent on its effect on autophagy. We studied the impact of JNK isoform downregulation in the HT29 colon adenocarcinoma cell line on hypoxia- and oxaliplatin-induced responses. Electron microscopic analyses demonstrated that both oxaliplatin- and hypoxia-induced formations of autophagosomes were reduced significantly in HT29 cells treated with the JNK inhibitor SP...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Vasilevskaya, I. A., Selvakumaran, M., Roberts, D., O'Dwyer, P. J. Tags: Signal Transduction Source Type: research

A Novel EGFR Extracellular Domain Mutant, EGFR{Delta}768, Possesses Distinct Biological and Biochemical Properties in Neuroblastoma
In conclusion, this is the first study to demonstrate that neuroblastoma express not only EGFRvIII, but also a novel EGFR extracellular domain deletion mutant, EGFR768. The EGFR768 also possesses distinct biologic and biochemical properties which might have therapeutic implications for neuroblastoma as well as other tumors expressing this novel mutant. Implications: Neuroblastoma expressed a novel EGFR mutant which possesses distinct biologic and biochemical properties that might have therapeutic implications. Mol Cancer Res; 14(8); 740–52. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Keller, J., Nimnual, A. S., Varghese, M. S., VanHeyst, K. A., Hayman, M. J., Chan, E. L. Tags: Oncogenes and Tumor Suppressors Source Type: research