Abstract IA08: Oxidative stress inhibits distant metastasis by human melanoma cells
Solid cancer cells commonly enter the blood and disseminate systemically but are highly inefficient at forming distant metastases for poorly understood reasons. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All melanomas had high frequencies of cells that formed subcutaneous tumors, but much lower percentages of cells that formed tumors after intravenous or intrasplenic transplantation, particularly among inefficient metastasizers. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established su...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Piskounova, E., Agathocleous, M., DeBerardinis, R. J., Morrison, S. J. Tags: Stem Cell of Origin: Oral Presentations - Invited Abstracts Source Type: research

Abstract B08: Altering cellular differentiation and energy metabolism by the mTORC1 inhibitor NPRL2
Nitrogen permease regulator-like 2 (NPRL2) is a component of an evolutionarily conserved complex that inhibits mTORC1 (mechanistic Target Of Rapamycin Complex 1) in response to amino acid insufficiency. The NPRL2 complex functions as a GTPase activating protein against the RAG proteins, which are located on the lysosomal surface and stimulate mTORC1 activity when bound to GTP. Since the loss of NPRL2 expression is frequently associated with different types of cancers, including renal and lung, our aim is to investigate the biological function of NPRL2 in vivo and determine how this pathway can contribute to cancer growth. ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Dutchak, P. A., Terpack, S., Tu, B. P. Tags: Signaling Pathways: Hippo/TOR: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA07: The effect of cell of origin on GBM phenotype
Current thinking about solid tumor biology is largely influenced by analysis of the large data sets afforded by modern genomic capabilities. In GBM, classification of tumors into four categories (proneural, neural, mesenchymal, and classic) relies on differential transcriptional profiles coupled with copy numbers, and mutational profiles. These approaches for example, imply EGFR receptor as a major driver of Classic sub-type whereas NF1 mutations are preferentially found in mesenchymal subtypes. Functional evidence that these molecular categories indeed reflect biologically different tumors remains to be proved. We have ge...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Parada, L. F. Tags: Stem Cell of Origin: Oral Presentations - Invited Abstracts Source Type: research

Abstract B07: Tead and AP1 coordinate transcription and motility in cancer cells
The Tead family transcription factors are the major mediators of the Hippo-Yap pathway. Although misregulation of Hippo signaling has been implicated in many human cancers, Tead dependent downstream transcriptional programs in cancer cells remain poorly understood. Here we characterize Tead4-mediated transcriptional networks in diverse cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 factors to coordinate target gene transcription. We find that the interaction of AP...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Liu, X., Li, H., Rajurkar, M., Cotton, J., Mercurio, A., Davis, R., Mao, J. Tags: Signaling Pathways: Hippo/TOR: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A07: Gene analysis maps HCC heterogeneity and orientates personalized therapy
Hepatocellular carcinoma (HCC) has variable prognosis depending both on the severity of underlying liver disease and of its biological characteristic. We recently identified, in a prospective series of HCCs at first presentation, a 5-genes transcriptomic signature, which accurately and significantly predicts growth speed and survival (Gut. 2015 Feb 9. pii:gutjnl-2014-308483. doi: 10.1136/gutjnl-2014-308483). This signature encounters 5 up-regulated genes (ANGPT2, DLL4, NETO2, ESM1, NR4A1), all associated with neo-angiogenesis. Such gene analysis prompted us to characterize further the molecular pathways underlying tumor ag...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Critelli, R. M., Milosa, F., Lei, B., Marzi, L., Condello, R., Turola, E., Maria, N. D., Maiorana, A., Giannelli, G., Villa, E. Tags: Cancer Niche / Cellular Interactions: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR06: The reemergence of neural crest progenitor identity is a key event in the initiation of melanoma from a field of cancer-prone melanocytes
Within a group of cancer-prone cells that harbor a shared oncogenic mutation, only rare clones transition to a malignant state. These rare and transient events occurring during cancer initiation remain incompletely understood, and we thus sought to visualize and molecularly characterize this crucial early step in oncogenesis of melanoma. We previously found that the zebrafish crestin gene, which specifically marks embryonic neural crest and normally turns off at three days of life, is specifically re-expressed in BRAFV600E/p53 mutant melanoma tumors in adult zebrafish. We cloned the crestin promoter/enhancer and developed ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Kaufman, C. K., Mosimann, C., Thomas, A., Fan, Z. P., Yang, S., Tan, J., Fogley, R. D., Rooijen, E. v., Hagedorn, E., Ciarlo, C., White, R., Matos, D., Puller, A.-C., Santoriello, C., Liao, E., Young, R. A., Zon, L. I. Tags: Stem Cell of Origin: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA06: Stem cells in mammalian epidermis
Multiple epidermal stem cell subpopulations in adult mouse skin have been identified over the last decade. Although they are all competent to give rise to all the different epidermal lineages following transplantation, wounding or genetic modification, under steady state conditions they maintain the epidermis in a compartmentalized manner. Stem cells in the lower hair follicle express LGR5, while stem cells in the upper follicle express LGR6 and cells in the junctional zone express LRIG1. In addition, a subset of stem cells in the interfollicular epidermis expresses LGR6. In my presentation I will discuss the consequences ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Watt, F. M. Tags: Stem Cell of Origin: Oral Presentations - Invited Abstracts Source Type: research

Abstract B06: Complex requirement of YAP and TAZ in gastrointestinal development and tumorigenesis
YAP and TAZ are the major intracellular mediators of Hippo signaling in mammals; however, the precise function of YAP/TAZ in gastrointestinal development and tumorigenesis remains poorly understood. By specific removal of YAP/TAZ from the developing endoderm and gastrointestinal tract, we find that YAP/TAZ are dispensable for Wnt signal transduction and normal gastrointestinal epithelial differentiation, but act as the direct TCF4 targets and downstream effectors during epithelial transformation. Surprisingly, our loss- and gain-of-function genetic analyses identify an essential role for YAP/TAZ in the gastrointestinal mes...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Cotton, J. L., Li, Q., Ma, L., Ip, T., Johnson, R., Mao, J. Tags: Signaling Pathways: Hippo/TOR: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A06: Exploring mechanisms of colorectal tumor radioresistance in organoids
Colorectal cancer is the third most common cancer in men and the second in women worldwide. It is currently proposed that a population of tumor stem cells that are resistant to radiotherapy leads to tumor recurrence. Accumulating evidence indicates that a transformed lgr5+ [leucine-rich-repeat-containing G-protein-coupled receptor 5] cell at the base of the colonic crypt represents the cell of origin of colorectal cancer. However, mechanisms underlying colorectal cancer radioresistance are not completely understood. The purpose of this study is to elucidate mechanisms of resistance to radiation of normal and tumor stem cel...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Martin, M. L., Hua, G., Zeng, Z., Paty, P. B. Tags: Cancer Niche / Cellular Interactions: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR05: Systematic forward genetic screens in haploid human cells reveal new players and regulatory mechanisms in Wnt signaling
Wnt signaling is at the core of animal development and regeneration. It controls cell proliferation, differentiation and survival. In humans, defective Wnt signaling leads to several forms of cancer, most notably colorectal cancer (CRC). A convergence of methodological advances enabled us to do a systematic forward genetic analysis of canonical Wnt signaling in human cells, revealing new players and regulatory mechanisms. Using HAP1 cells, a haploid human cell line, we conducted a set of genome-wide screens to interrogate the Wnt pathway under normal and pathological conditions. We constructed a HAP1 line harboring a Wnt-r...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Lebensohn, A. M., Dubey, R., Neitzel, L. R., Tacchelly, O., Marceau, C. D., Bahrami, Z., Hansen, A. G., Ahmed, Y., Lee, E., Carette, J., Rohatgi, R. Tags: Signaling Pathways: Wnt: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA05: Polycomb repressive complex-2 is a barrier to Kras-driven inflammation and epithelial-mesenchymal transition in non-small cell lung cancer
Polycomb repressive complexes (PRC) are frequently implicated in human cancer acting either as oncogenes or tumor suppressors. Here we show that PRC2 is a critical regulator of Kras-driven non-small-cell lung cancer (NSCLC) progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances Kras-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell autonomous epithelial-to- mesenchymal transition (EMT) program leading to an invasive mucinous adenocarci...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Serresi, M., Gargiulo, G., Proost, N., Siteur, B., Cesaroni, M., Koppens, M., Xie, H., Sutherland, K., Hulsman, D., Citterio, E., Orkin, S., Berns, A., Lohuizen, M. v. Tags: Epigenetics: Oral Presentations - Invited Abstracts Source Type: research

Abstract B05: Mesenchymal-driven hedgehog signaling drives tumor cell growth and is a potential new target for triple-negative breast cancer
Triple negative breast cancer (TNBC) is a clinical therapeutic challenge due to the lack of receptors for estrogen, progesterone, and human epidermal growth factor receptor 2 which limits treatment options to chemotherapy and radiation. With current standard therapy less than 30% will survive the 5-year remission rate, especially Hispanic and African-American women where TNBC is more frequent and has the lowest (500 samples) show a strong correlation among TNBC patients and mesenchymal-driven Hh signaling in>80% of samples. We evaluated the distribution of mesenchymal cell-sub-types and stem cells among the sub-set of b...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Domenech, M., Ramos, K. P., Torres, W., Boria, F. Tags: Signaling Pathways: Hedgehog: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR04: Germline loss of PK-M2 promotes metabolic syndrome and hepatocellular carcinoma
This study will allow us to elucidate the distinct cell-intrinsic and cell-extrinsic roles of PK-M2 in both maintaining normal systemic metabolism and aberrant proliferation in the context of cancer.This abstract is also presented as Poster B25.Citation Format: Talya L. Dayton, Vasilena Gocheva, Kathryn M. Miller, William J. Israelsen, Clary B. Clish, Arjun Bhutkar, Shawn M. Davidson, Alba Luengo, Matthew G. Vander Heiden, Tyler E. Jacks. Germline loss of PK-M2 promotes metabolic syndrome and hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Dayton, T. L., Gocheva, V., Miller, K. M., Israelsen, W. J., Clish, C. B., Bhutkar, A., Davidson, S. M., Luengo, A., Heiden, M. G. V., Jacks, T. E. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B04: IKBKE integrates Gli and mTOR-AKT activation during Kras-induced pancreatic tumorigenesis
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here we show that the non-canonical IB-related kinase, IKBKE, acts downstream of the Gli transcription factors and engages in reciprocal regulation of Gli signaling in pancreatic cancer cells. We find that loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic specific KRAS activation. Mechanistically, IKBKE does not play a major role in NF-B activation in pancreatic cancer; but is critical for AKT activation in vivo. Moreover, we find that IKBKE promotes rea...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Rajurkar, M., Fernandez-Zapico, M., Lewis, B., Mao, J. Tags: Signaling Pathways: Hedgehog: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A04: Alpha-1-Antitrypsin is a secreted protein driven by mutant p53 and associated with EMT, migration and invasion in-vivo
In this study, we investigated the global impact of mutant p53 induced secretome on cancer cell proteome. A1AT is a secreted protein encoded by SERPINA1, a secreted serine protease inhibitor that neutralizes the effect of proteases, and A1AT involvement in mutant p53 driven tumorigenesis is unclear.Methodology: We have developed a panel of H1299 lung adenocarcinoma derivatives that can inducibly re-express various mutant p53 proteins into a p53 null background. Expression levels were assessed by western blot analyses and real time PCR. Using iTRAQ (isobaric tag for relative and absolute quantification) and Liquid chromatog...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Shakya, R., Turner, A. G., Cooper, W., Lokman, N. A., Ricciardelli, C., Tarulli, G., Neilsen, P. M., Callen, D. F. Tags: Cancer Niche / Cellular Interactions: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B03: Developmental paracrine signaling pathways promote prostate cancer progression
Classic experiments in prostate embryology showed more than 30 years ago that reciprocal paracrine signals between the developing prostatic epithelium and mesenchyme were an essential feature of prostatic branching morphogenesis. Parallel research on the role of epithelial-stromal interactions during the progression of prostate cancer also showed that one or more stromal-to-epithelial paracrine signaling pathways play key roles in promoting disease progression in prostatic adenocarcinomas. Modeling these paracrine interactions involving multiple cell types for mechanistic studies in vitro can be difficult using traditional...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Powers, G., Su, X., Beebe, D., Marker, P. Tags: Signaling Pathways: Hedgehog: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A03: The effects of the cellular microenvironment on medulloblastoma metastasis
Medulloblastoma (MB) is the most common pediatric brain tumor, known to be highly malignant and invasive within the brain as well as extraneural locations. The mechanisms inducing MB metastasis and dissemination are not completely understood. Astrocytes, the most abundant cell type in the brain, have been shown in our lab to secrete factors that induce breast cancer brain metastasis (Wang et al., 2013). In addition to astrocytes, many brain cell types have also been implicated in the malignancy of brain tumors, including microglia, pericytes, and endothelial cells as part of the neurovascular unit. The overall goal of this...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Gronseth, E., Wang, L., Koceja, C., Ramchandran, R. Tags: Cancer Niche / Cellular Interactions: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR02: The SWI/SNF component Arid1a regulates regenerative capacity and carcinogenesis in a dose-dependent fashion
It is unclear if regenerative capacity can be dissociated from cancer risk, a question that is highly relevant for liver carcinogenesis. Frequent SWI/SNF and Arid1a loss-of-function mutations suggest tumor suppressive roles, but the functional impact of these mutations in tissue homeostasis and cancer is unclear. Mice without Arid1a possessed improved healing abilities after an array of injuries. After liver resection, chemical hepatocyte injury, and toxic bile duct injury, Arid1a deficient livers exhibited increased regeneration, reduced tissue damage, and improved organ function. Moreover, global homozygous Arid1a loss p...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Sun, X., Wang, S., Maples, T., Li, L., Nguyen, L., Chuang, J.-C., Sorouri, M., Zhang, S., Wu, L., Celen, C., Zhu, H. Tags: Epigenetics: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B02: Sonic hedgehog signaling in neuronal migration and tumorigenesis
Conclusion: We propose that Shh signaling prevents GNPs from exiting the EGL by maintaining the expression of Siah2 in a Ras-Erk dependent pathway. Differentiated CGNs retract the primary cilia, hence becoming insensitive to Shh allowing them to downregulate Siah2 to initiate GZ exit. Aberrant Shh signaling disrupts this developmental program by maintaining GNPs in the germinal zone which we postulate to be the initial step in Shh-MB tumorigenesis.Citation Format: Taren Ong, David J. Solecki. Sonic hedgehog signaling in neuronal migration and tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Develo...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Ong, T., Solecki, D. J. Tags: Signaling Pathways: Hedgehog: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A02: A kinome-wide RNAi screen in Drosophila glia and human GBM models reveals Stk17A drives neoplastic glial proliferation and migration
Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, are highly proliferative, diffusely invasive, and incurable by current therapies. Genetic and molecular analyses reveal that GBMs frequently harbor activating mutations in the EGFR receptor tyrosine kinase (EGFR) and Pi-3 kinase (PI3K) signaling pathways. While the ability of these mutations to drive gliomagenesis has been verified in mouse models, current data also indicate that EGFR and PI3K signaling cooperates with as yet unknown factors to drive its invasive pathology and therapeutic resistance in GBM. To identify such factors, we performed ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Wardwell-Ozgo, J., Mosley, C., Kornblum, H., Read, R. Tags: Cancer Niche / Cellular Interactions: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR01: 3D enhancer clusters in the response to Wnt-driven colorectal cancer
Super-enhancers are clusters of enhancers that drive expression of genes key to development and cancer. We recently showed that super-enhancers and their target genes occur within DNA loops bounded by CTCF proteins. These chromosome structures constrain the activities of enhancers to genes that occur within the same loop, and were thus called insulated neighborhoods. Recent studies have shown that signaling pathways converge on super-enhancers, but the effect of signaling-mediated gene activation has yet to be investigated in the context of insulated neighborhood structure and function. We used a model of Wnt-pathway activ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Schuijers, J., Day, D. S., Saint-Andre, V., Young, R. A. Tags: Epigenetics: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA01: Wnt signaling stem cell control and cancer
Our laboratory is interested in the growth, development and integrity of animal tissues, with a focus on stem cells. Wnt signaling is widely implicated in stem cell control, as a mechanism to regulate the number of stem cells in tissues, Using various cell labeling methods, we have described novel populations of stem cells in various tissues, including in the liver. In that tissue, we found that hepatocytes that reside in the pericentral domain of the liver demonstrate stem cell behavior. Although these cells are functional hepatocytes, they are diploid and thus differ from the mostly polyploid mature hepatocyte population...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Nusse, R. Tags: Signaling Pathways: Wnt: Oral Presentations - Invited Abstracts Source Type: research

Abstract A01: Investigating clonal heterogeneity and transcriptional vulnerabilities in latent metastasis
Most cancer deaths are due to the poorly understood process of metastasis, which is seeded by disseminated tumor cells (DTCs). DTCs exhibit exceedingly variable latency, outgrowing immediately or lying dormant for months to years in a viable state of mass dormancy or replicative quiescence. The mechanisms enabling DTCs to survive and resist therapy are poorly understood. We have recently derived several models of latent metastasis that default to a slow-cycling state under stress, reserve the capacity for tumor-initiation, and evade immune surveillance. These DTCs resemble progenitor stem cell populations at the molecular ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Laughney, A. M., Malladi, S., Macalinao, D., Massague, J. Tags: Cancer Niche / Cellular Interactions: Poster Presentations - Proffered Abstracts Source Type: research

SGK and Multiple Myeloma
To assess the role of the serum and glucocorticoid-regulated kinase (SGK) kinase in multiple myeloma, we ectopically expressed wild type or a phosphomimetic version of SGK into multiple myeloma cell lines. These cells were specifically resistant to the ER stress inducers tunicamycin, thapsigargin, and bortezomib. In contrast, there was no alteration of sensitivity to dexamethasone, serum starvation, or mTORC inhibitors. Mining of genomic data from a public database indicated that low baseline SGK expression in multiple myeloma patients correlated with enhanced ability to undergo a complete response to subsequent bortezomib...
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Hoang, B., Shi, Y., Frost, P. J., Mysore, V., Bardeleben, C., Lichtenstein, A. Tags: Signal Transduction Source Type: research

KLF4 and Colonic Tumor Suppression
This study highlights the important role of KLF4 in suppressing the development of colonic neoplasia under different tumor-promoting conditions. Implications: The study demonstrates that KLF4 plays a significant role in the pathogenesis of colorectal neoplasia. Mol Cancer Res; 14(4); 385–96. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Ghaleb, A. M., Elkarim, E. A., Bialkowska, A. B., Yang, V. W. Tags: Oncogenes and Tumor Suppressors Source Type: research

Prostate Cancer Stroma Lacks Genomic Aberrations
This study evaluates the nuclear and mitochondrial DNA integrity of prostate carcinoma cells, CAS, matched benign epithelium and benign epithelium–associated stroma by whole-genome copy-number analyses, targeted sequencing of TP53, and FISH. Array comparative genomic hybridization (aCGH) of CAS revealed a copy-neutral diploid genome with only rare and small somatic copy-number aberrations (SCNA). In contrast, several expected recurrent SCNAs were evident in the adjacent prostate carcinoma cells, including gains at 3q, 7p, and 8q, and losses at 8p and 10q. No somatic TP53 mutations were observed in CAS. Mitochondrial ...
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Bianchi-Frias, D., Basom, R., Delrow, J. J., Coleman, I. M., Dakhova, O., Qu, X., Fang, M., Franco, O. E., Ericson, N. G., Bielas, J. H., Hayward, S. W., True, L., Morrissey, C., Brown, L., Bhowmick, N. A., Rowley, D., Ittmann, M., Nelson, P. S. Tags: Genomics Source Type: research

miR-155 Overexpression Promotes Genomic Instability
miR-155 is an oncogenic miRNA that is often overexpressed in cancer and is associated with poor prognosis. miR-155 can target several DNA repair factors, including RAD51, MLH1, and MSH6, and its overexpression results in an increased mutation frequency in vitro, although the mechanism has yet to be fully understood. Here, we demonstrate that overexpression of miR-155 drives an increased mutation frequency both in vitro and in vivo, promoting genomic instability by affecting multiple DNA repair pathways. miR-155 overexpression causes a decrease in homologous recombination, but yields a concurrent increase in the error-prone...
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Czochor, J. R., Sulkowski, P., Glazer, P. M. Tags: DNA Damage and Repair Source Type: research

miRNA-137/DCLK1 Axis Regulates Colon Cancer Stem Cells
miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused on miRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colon CSCs (EpCAM+/CD44+/CD66a–) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1 (DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive...
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Sakaguchi, M., Hisamori, S., Oshima, N., Sato, F., Shimono, Y., Sakai, Y. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Glucose Metabolism in Prostatic SCNC
In conclusion, this study suggests different pathways of glucose metabolism contribute to the disparate biologic behaviors of these two tumor types. Implications: CD44 is an important regulator of glucose metabolism in small cell neuroendocrine carcinoma and may be an important therapeutic target. Mol Cancer Res; 14(4); 344–53. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Li, W., Cohen, A., Sun, Y., Squires, J., Braas, D., Graeber, T. G., Du, L., Li, G., Li, Z., Xu, X., Chen, X., Huang, J. Tags: Cell Death and Survival Source Type: research

Predicting Prognosis in Liposarcoma
This study uses integrative analyses to systematically define the transcriptional regulatory programs associated with liposarcoma. Likewise, computational methods are used to identify regulatory programs associated with different liposarcoma subtypes, as well as programs that are predictive of prognosis. Further analysis of curated gene sets was used to identify prognostic gene signatures. The integration of data from a variety of sources, including gene expression profiles, transcription factor–binding data from ChIP-Seq experiments, curated gene sets, and clinical information of patients, indicated discrete regulat...
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Cheng, C., Lou, S., Andrews, E. H., Ung, M. H., Varn, F. S. Tags: Cell Cycle and Senescence Source Type: research

BET Bromodomain Inhibitors in Treatment of Prostate Cancer
Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7...
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Asangani, I. A., Wilder-Romans, K., Dommeti, V. L., Krishnamurthy, P. M., Apel, I. J., Escara-Wilke, J., Plymate, S. R., Navone, N. M., Wang, S., Feng, F. Y., Chinnaiyan, A. M. Tags: Rapid Impact Source Type: research

Understanding TERT Promoter Mutations
Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. Although TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT ...
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Bell, R. J. A., Rube, H. T., Xavier-Magalhaes, A., Costa, B. M., Mancini, A., Song, J. S., Costello, J. F. Tags: Review Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

SGEF Promotes Glioblastoma Cell Survival
Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide, GB tumors develop treatment resistance and ultimately recur. Impaired response to treatment occurs rapidly, conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance to develop targeted therapies to combat this refractory disease. Previous observations indicated that SGEF (ARHGEF26), a RhoG-specific guanine nucleotide exchang...
Source: Molecular Cancer Research - March 14, 2016 Category: Cancer & Oncology Authors: Ensign, S. P. F., Roos, A., Mathews, I. T., Dhruv, H. D., Tuncali, S., Sarkaria, J. N., Symons, M. H., Loftus, J. C., Berens, M. E., Tran, N. L. Tags: Signal Transduction Source Type: research

Kinase Alterations in Colorectal Carcinoma
Targeted therapy for metastatic colorectal carcinoma consists of anti-EGFR therapy for patients with RAS/RAF wild-type tumors. However, the response rate remains low, suggesting the presence of alternative drivers possibly also representing potential therapeutic targets. We investigated receptor tyrosine kinase (RTK) alterations and MAP2K1 (MEK1) mutations in a large cohort of colorectal carcinoma patients studied by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and The Cancer Genome Atlas, focusing on amplifications, fusions, and hotspot mutations in RTK genes and MAP2K1. RTK gene amp...
Source: Molecular Cancer Research - March 14, 2016 Category: Cancer & Oncology Authors: Hechtman, J. F., Zehir, A., Yaeger, R., Wang, L., Middha, S., Zheng, T., Hyman, D. M., Solit, D., Arcila, M. E., Borsu, L., Shia, J., Vakiani, E., Saltz, L., Ladanyi, M. Tags: Oncogenes and Tumor Suppressors Source Type: research

CAFs Regulate Collagen Cross-Linking
Intratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how collagen cross-linking is regulated in epithelial tumors. To address this question, we used KrasLA1 mice, which develop lung adenocarcinomas from somatic activation of a KrasG12D allele. The lung tumors in KrasLA1 mice were highly fibrotic and contained cancer-associated fibroblasts (CAF) that produced collagen and generated stiffness in collagen gels. In xenograft tumors generated by injection of wild-type mice with lung adenocarcinoma cells alone or in combination with CAFs, the total concentration of col...
Source: Molecular Cancer Research - March 14, 2016 Category: Cancer & Oncology Authors: Pankova, D., Chen, Y., Terajima, M., Schliekelman, M. J., Baird, B. N., Fahrenholtz, M., Sun, L., Gill, B. J., Vadakkan, T. J., Kim, M. P., Ahn, Y.-H., Roybal, J. D., Liu, X., Parra Cuentas, E. R., Rodriguez, J., Wistuba, I. I., Creighton, C. J., Gibbons, Tags: Oncogenes and Tumor Suppressors Source Type: research

Proteomic Characterization: HNSCC Patient-Derived Xenografts
Despite advances in treatment approaches for head and neck squamous cell carcinoma (HNSCC), survival rates have remained stagnant due to the paucity of preclinical models that accurately reflect the human tumor. Patient-derived xenografts (PDX) are an emerging model system where patient tumors are implanted directly into mice. Increased understanding of the application and limitations of PDXs will facilitate their rational use. Studies to date have not reported protein profiles of PDXs. Therefore, we developed a large cohort of HNSCC PDXs and found that tumor take rate was not influenced by the clinical, pathologic, or pro...
Source: Molecular Cancer Research - March 14, 2016 Category: Cancer & Oncology Authors: Li, H., Wheeler, S., Park, Y., Ju, Z., Thomas, S. M., Fichera, M., Egloff, A. M., Lui, V. W., Duvvuri, U., Bauman, J. E., Mills, G. B., Grandis, J. R. Tags: Genomics Source Type: research

KRAS-Regulated miR-31 Modulates Invasion Migration
Activating KRAS mutations are nearly ubiquitous in pancreatic cancer occurring in more than 95% of clinical cases. miRNAs are small noncoding RNAs that regulate gene expression by binding sequences within the 3'UTRs of target mRNAs. An integral role for miRNAs in cancer pathogenesis is well established; however, the role of miRNAs in KRAS-mediated tumorigenesis is poorly characterized. Here it is demonstrated that expression of miR-31 is coupled to the expression of oncogenic KRAS and activity of the MAPK pathway. miR-31 is highly expressed in patient-derived xenografts and a panel of pancreatic and colorectal cancer cells...
Source: Molecular Cancer Research - March 14, 2016 Category: Cancer & Oncology Authors: Kent, O. A., Mendell, J. T., Rottapel, R. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Targeting the Adaptive Hypoxic Response in Multiple Myeloma Cells
Multiple myeloma is incurable and invariably becomes resistant to chemotherapy. Although the mechanisms remain unclear, hypoxic conditions in the bone marrow have been implicated in contributing to multiple myeloma progression, angiogenesis, and resistance to chemotherapy. These effects occur via adaptive cellular responses mediated by hypoxia-inducible transcription factors (HIF), and targeting HIFs can have anticancer effects in both solid and hematologic malignancies. Here, it was found that in most myeloma cell lines tested, HIF1α, but not HIF2α expression was oxygen dependent, and this could be explained b...
Source: Molecular Cancer Research - March 14, 2016 Category: Cancer & Oncology Authors: Mysore, V. S., Szablowski, J., Dervan, P. B., Frost, P. J. Tags: Cell Death and Survival Source Type: research

Aspirin and Salicylic Acid Downregulate Cyclin A2/CDK2
In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The downregulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. First, inclusion of s...
Source: Molecular Cancer Research - March 14, 2016 Category: Cancer & Oncology Authors: Dachineni, R., Ai, G., Kumar, D. R., Sadhu, S. S., Tummala, H., Bhat, G. J. Tags: Cell Cycle and Senescence Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - March 14, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

Abstract A72: The E3-ligase E6AP represses breast cancer metastasis through regulation of ECT2-Rho-GTPases signaling
We report that E6AP suppresses breast cancer invasiveness, colonisation and metastasis in mice and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for with basal breast cancer. E6AP regulates actin cytoskeletal remodelling via regulation of Rho-GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho-GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodelling through ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Mansour, M., Haupt, S., Chan, A.-L., Godde, N., Rizzitelli, A., Loi, S., Caramia, F., Deb, S., Takano, E. A., Bishton, M., Johnstone, C., Levav-Cohen, Y., Jiang, Y.-H., Yap, A. S., Fox, S., Bernard, O., Anderson, R., Haupt, Y. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A71: HDAC6 activity is a non-oncogene addiction hub for in inflammatory breast cancers
Inflammatory breast cancer (IBC) is the most lethal form of breast cancer (~5% of all breast cancers). Almost all women with primary IBC have lymph node involvement, and at diagnosis approximately 25% have already distant metastases. Remarkably, the 5-year survival rate is only 40%, compared to the 85% survival rate among non-IBC patients. Despite its lethality, IBC remains poorly understood, and is the only breast cancer form for which mortality has continued to increase during the last 20 years. There are no current targeted therapies specific for IBC and systemic disease management relies mainly on chemotherapy.Due to t...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Putcha, P., Yu, J., Rodriguez-Barrueco, R., Califano, A., silva, j. Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B70: p16 and 9p21 deletion are largely unrelated but linked to unfavorable tumor phenotype in breast cancer
Overexpression of the p16 tumor suppressor, but also deletion of its gene locus 9p21, has been linked to unfavorable tumor phenotype and poor patient outcome in breast cancer. To better understand these seemingly contradictory observations, and the prognostic impact of p16 expression and 9p21 deletion in breast cancer, we analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a CDKN2A-specific probe and by p16 immunohistochemistry. p16 immunostaining was typically uniform and considered weak in 25.6%, moderate in 7.1%, and strong in 12.7% of 1,684 analyzable cancers....
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Lebok, P., Roming, M., Kluth, M., Koop, C., Oezden, C., Taskin, B., Hussein, K., Lebeau, A., Witzel, I., Mahner, S., Geist, S., Paluchowski, P., Wilke, C., Heilenkoetter, U., Mueller, V., Simon, R., Sauter, G., Terracciano, L., Krech, R., Assen, A. v. d., Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A70: Akt2 gain or Akt1 loss drives invasion and aggressiveness in breast cancer
Despite the improvement in the early diagnosis and the use of modern therapies, breast cancer is the second cause of death, after lung cancer, in women around the world, and this is mainly due to metastasis development distant organs.PI3K/Akt pathway is deregulated in almost 50% of breast carcinomas, and is associated to therapy resistance. Currently, there are increasing clinical trials that combine endocrine treatments with PI3K/Akt inhibitors to delay tumor resistance and to avoid tumor progression. However, these inhibitors do not distinguish between the isoform specific function of Akt1, Akt2 and Akt3. Several evidenc...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Perrone, C., Riggio, M., May, M., Polo, M. L., Rodriguez, J., Kaen, D. L., Lanari, C., Novaro, V. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B69: Acquisition and maintenance of anti-Her2 target therapies resistance in breast cancer: Role of fibrobroblasts
Conclusion: These results highlight the importance of microenvironment in supporting tumor progression after chemotherapy.Citation Format: Patricia Fernandez-Nogueira, Mario Mancino, Gemma Fuster, Estel Enreig, Elisabeth Ametller, Paloma Bragado, Vanessa Almendro, Pere Gascon. Acquisition and maintenance of anti-Her2 target therapies resistance in breast cancer: Role of fibrobroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B69. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Mancino, M., Fuster, G., Enreig, E., Ametller, E., Bragado, P., Almendro, V., Gascon, P. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B68: Contributions of STAT3 to pro-tumorigenic alterations within the microenvironment during mammary tumorigenesis
Inflammation has long been recognized as a possible trigger that contributes to tumor initiation. Numerous studies have shown that cells of both the innate and adaptive immune systems are able to support tumor formation and growth through secretion of growth factors and cytokines and by actively shielding the tumor from wider immune surveillance. As a result, inflammation is generally linked to worse patient outcome. However, depending on factors such as tumor size, extracellular matrix, and the complex composition of immune cell infiltrates, inflammation can promote both pro- and anti-tumor properties. Our studies focus o...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Chuntova, P., Bohrer, L. R., Schwertfeger, K. L. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A68: Penfluridol suppresses triple-negative breast cancer metastasis to brain by inhibiting integrin signaling
Breast cancer is the second leading cause of cancer related deaths in US. Breast tumor metastasis to brain is major cause of deaths. Brain metastasis of triple negative breast cancer cells (TNBC) is highly resistant to current therapies and is a cause of reduced survival rates in patients. In current study, we evaluated penfluridol, a first generation, highly potent antipsychotic drug against three different highly aggressive TNBC cell line. The IC50 of penfluridol was around 6 µM in 4T1, MDA-MB-231 and HCC-1806, breast cancer cells respectively. Our result showed that the expression of integrinβ4, integrin&alph...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Ranjan, A., Gupta, P., Srivastava, S. K. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B67: CD4 Th1 cytokines synergize with HER-2/HER-3 blockade to induce tumor senescence and apoptosis in both HER-2 sensitive and resistant breast cancer cells
Conclusions: Our results establish a role for Th1 cytokines IFN- and TNF-α in inducing tumor senescence and apoptosis in both sensitive and resistant HER-2 expressing cells that is dramatically augmented by HER-2/HER-3 blockade. An effective CD4 Th1 response, combined with HER-2 and HER-3 blockade can significantly drive tumor senescence and apoptosis and should be readily explored as non-cross-reactive therapy to effectively eliminate residual cancer cells and prevent recurrence in HER-2pos breast cancer.Citation Format: Cinthia Rosemblit, Brian J. Czerniecki. CD4 Th1 cytokines synergize with HER-2/HER-3 blockade to...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Rosemblit, C., Czerniecki, B. J. Tags: Tumor Microenvironment and Immunotherapy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A67: Lack of androgen receptor expression correlates with high expression of ALDH1 and poor overall and 5-year disease free survival in patients with invasive breast cancer
Introduction: A sub-population of cells referred to as cancer stem cells has been identified utilizing specific markers such as aldehyde dehydrogenase 1 (ALDH1) amongst others in solid tumors including breast cancers. Evidence from in vitro studies has shown that high ALDH1 expression identifies tumorigenic cell population which is capable of self-renewal and generating tumors which recapitulate the heterogeneity of the primary tumors. Expression of androgen receptor is present in 70-90% cases of invasive breast cancers at a frequency that is higher than the expression of estrogen or progesterone receptors. However, progno...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Riaz, N., Idress, R., Habib, S., Naqvi, S. Z., Khan, S. M., Siddiqui, A. A., Lalani, E.-N. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research