Abstract B33: Alterations in the binding of Meis proteins to HoxB13 or to DNA promote prostate cancer progression
Conclusions: Our data indicate that full length Meis protein levels are consistently lower in cancer as compared to normal tissues, and are decreased to a greater extent in more aggressive cancers. Full length Meis proteins may act as tumor suppressors while the homeodomain-less isoforms may act as dominant negatives. Further, we demonstrate a regulatory interaction between Meis expression and AR signaling, providing evidence for a downstream role of Meis proteins in the most important pathway for PrCa progression. We are the first to investigate the functional differences of these isoforms in the context of PrCa. An under...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Brechka, H., Bhanvadia, R., Griend, D. V. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A33: A role of SET/I2PP2A in HNSCC angiogenesis and tumor-promoting microenvironment
This study addressed a potential role of SET/I2PP2A protein on angiogenesis and immune response in head and neck squamous cell carcinoma (HNSCC). A HNSCC cell line with stable SET knockdown (HN12shSET/HN12shControl), previously established in our laboratory, was used to perform (1) qPCR array analysis of genes related to angiogenesis (Qiagen), and (2) tube-formation assay using Human Umbilical Vein Endothelial cells (HUVEC) cultured with HN12shSET cells conditioned medium. Moreover, several chemokines and cytokines were analyzed by Multi-Analyte ELISA array (Qiagen), and the specific levels of TGF-B1 and RANTES were valida...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Sobral, L., Santos, L. F., Curti, C., Leopoldino, A. M. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA32: Identification and therapeutic targeting of poor prognosis subtypes in colorectal cancer
About 40-50% of Colorectal Cancer (CRC) patients with locally advanced disease show resistance to therapy and develop recurrent cancer over the course of their treatment. Current CRC staging based on histopathology and imaging has a limited ability to predict prognosis. A major advance has been the elaboration of molecular classifications based on global gene expression profiles, which have defined CRC subtypes displaying resistance to therapy and poor prognosis. We have recently evaluated these molecular classification systems and discovered that their predictive power arises from genes expressed by stromal cells rather t...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Batlle, E. Tags: Signaling Pathways: BMP/TGFbeta/SMAD: Oral Presentations - Invited Abstracts Source Type: research

Abstract B32: Role of membrane lipids in colonocytes maturation revealed by mass spectrometry-base imaging techniques
The epithelial layer of the human colon form finger-like invaginations into the underlying connective tissue of the lamina propria to establish the basic functional unit of the intestine, the crypt. Adult stems cells, located at the crypt base, proliferate and differentiate into the mature lineages of the surface epithelium. It is know that any alteration of the pathways regulating stem cell renewal leads to tumor formation. In this context, little is know about how processes as cell differentiation or tumorigenesis affect one of the critical components of a cell: the plasma membrane. Thus, plasma membrane by regulating it...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Bestard-Escalas, J., Jone, G., Maimo-Barcelo, A., Roberto, F., Lage, S., Lopez, D. H., Reigada, R., Khorrami, S., Ginard, D., Fernandez, J. A., Barcelo-Cobliijn, G. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA31: Control of TGF-{beta} responsiveness and epithelial plasticity
TGF-β signaling inhibits cell growth in epithelial cells and thus acts as tumor suppressor, yet increased TGF-β signaling often promotes cancer progression through effects on the tumor micro-environment and effects on the carcinoma cells that can lead to epithelial plasticity responses and increased invasion. The responsive epithelial or carcinoma cells can regulate their cell surface levels of TGF-β receptors, and thus enhance their responses to TGF-β. In addition to transcription control of TGF-β receptor expression, the cells can rapidly mobilize TβRII and TβRI from a large intracellul...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Derynck, R., Budi, E., Muthusamy, B.-P., Katsuno, Y., Du, D. Tags: Signaling Pathways: BMP/TGFbeta/SMAD: Oral Presentations - Invited Abstracts Source Type: research

Abstract B31: In utero exposure to bisphenol A induces reprogramming of mammary development and tumor risk in MMTV-erbB-2 transgenic mice
This study aimed to investigate the effects of in utero exposure to BPA on mammary tumor development in MMTV-erbB-2 transgenic mice, which exemplifies a scenario of gene-environmental interaction. Since erbB-2 is amplified/overexpressed in approximately 30% of breast cancer, which has been associated with poor prognosis and therapeutic resistance, use of this clinically relevant mammary tumor model is of high translational value. In this study, pregnant MMTV-erbB-2 mice were subcutaneously injected with 0, 50 ng, 500 ng and 250 μg/Kg body weight BPA daily between day 13 and day 19 of gestation. We found that in utero ex...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Ma, Z., Parris, A., Yang, X. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA30: BAF complex structure and function in development and disease
Recent exon-wide sequencing studies in human cancer have revealed a striking frequency of mutations in the genes encoding subunits of the mSWI/SNF (BAF) ATP-dependent chromatin remodeling complexes we recently determined these mutations to be broadly recurrent in over 20% of all human cancers. To investigate the underlying mechanism, our group has studied rare, genomically well-defined cancer types, namely human synovial sarcoma (SS) in which 100% of tumors have a precise translocation involving a specific subunit, SS18, and BAF47-deficient malignant rhabdoid tumors. The utility of these disease settings has provided us wi...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Kadoch, C. Tags: EMT and Plasticity: Oral Presentations - Invited Abstracts Source Type: research

Abstract B30: Regulation of proliferation and differentiation by atonal homolog 1 phosphorylation
Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor that acts as a tumor-suppressor as well as drives the differentiation of intestinal progenitor cells. Phosphorylation of Atoh1 is an important regulatory mechanism of its activity; proteins of the bHLH family can be phosphorylated by cyclin-dependent kinases during the cell cycle, which affects their differentiation-driving potential.We generated a colon cancer cell line model to investigate site-specific phosphoregulation of Atoh1. A mutant Atoh1, which has multiple serine/threonine residues changed to alanine at serine-proline (SP) and threo...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Tomic, G., Winton, D. J., Philpott, A. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A30: AKT activation as a mechanism of escape from TGF{beta}-mediated lethal EMT
Frequent inactivation of transforming growth factor β (TGFβ) pathway core components in pancreatic ductal adenocarcinoma (PDA), especially the transcription factor SMAD4, suggests that TGFβ signaling is tumor suppressive in the pancreas. Yet, 50% of PDA retains an intact core TGFβ pathway, suggesting that there are mechanisms by which these tumors escape TGFβ-mediated tumor suppression. In unpublished work, we have delineated a mechanism for TGFβ-mediated tumor suppression via a lethal epithelial-mesenchymal transition (EMT). Based on clinical and in vitro evidence that AKT activation may supp...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Huang, Y.-H., David, C., Massague, J. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA29: Identifying epithelial morphogenesis inhibitors in neural crest development and cancer
The epithelial to mesenchymal transition (EMT) is a highly conserved morphogenesis program that is essential for re-shaping and mobilizing epithelial cells during gastrulation, neural crest development and tissue regeneration. In cancer cells, EMT induction promotes acquisition of invasive cellular morphologies, stem cell-like properties and pro-survival mechanisms, which contribute to disease progression, therapy resistance and decreased overall survival. The identification of compounds that block or reverse EMT therefore represents an important therapeutic strategy to prevent cancer invasion and eradicate disseminated tu...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Jimenez, L., Whatcott, C., Wang, J., Warner, S., Morrison, M., Bearss, D., Stewart, R. A. Tags: EMT and Plasticity: Oral Presentations - Invited Abstracts Source Type: research

Abstract B29: Snail regulates extracellular matrix-mediated VEGFR3 expression in developmental and tumor angiogenesis
Snail family is a zinc finger transcription factor and involved in epithelial branching morphogenesis and EMT by altering the ability of polarity, motility, and adhesion. The expression of Snail family in developing and tumor vessels has been suggested, however, the precise expression pattern and cellular function of Snail remain to be unclear. We identified Snail as an angiogenic regulator through inducing VEGFR3 under extracellular matrix (ECM)-meditated signalings. Snail was upregulated in the postnatally developing retinal endothelial cells (ECs) and in the vessels lining ductal breast tumors. In vitro endothelial spro...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Park, J. A., Lee, H.-Y., Kwon, Y.-G. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A29: JNK contributes to BMP loss induced intestinal tumorigenesis in Drosophila
Genetic instability and mutations are contributed to colon cancer development. For instance, loss of intestinal BMP signaling through mutation on SMAD4 and BMPR1A is a prominent cause of gastrointestinal cancers. The BMP pathway functions as a negative regulator of crypts and is taken to be essential for terminal differentiation. However the genetic causes and molecular mechanism of BMP loss induced tumorigenesis remains largely unknown. Here, we used Drosophila intestinal tumors generated by suppressing BMP/Dpp signaling as a model to investigate the genetic mutations are essential for tumor development. We found BMP loss...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Zhou, J., Boutros, M. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA28: Epigenetic heterogeneity in breast cancer
Heterogeneity of cancer cells between and within tumors is a major obstacle toward understanding and treatment of cancers. Variability of epigenetic states is one of the major contributor to both intertumor and intratumor heterogeneity. In breast cancer luminal and basal-like breast tumors have very different molecular and clinical profiles. However, even in individual tumors there is variability among cells for these features. The determinants of luminal cell phenotypes are fairly well understood and major transcriptional regulators have been identified. In contrast, transcriptional determinants of basal-like breast tumor...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Polyak, K. Tags: EMT and Plasticity: Oral Presentations - Invited Abstracts Source Type: research

Abstract B28: The stem cell gene ABCB5 mediates colorectal cancer resistance to apoptosis
Cancer stem cells (CSC) responsible for disease progression and therapeutic resistance have been identified in several human malignancies, including colorectal cancer (CRC). However, the molecular mechanisms through which CSC drive tumor growth are incompletely understood. ABCB5, a member of the ATP-binding cassette superfamily of active transporters, serves as a CSC-specific multidrug resistance mechanism in diverse human malignancies. Additionally, ABCB5 has recently been demonstrated to function as an anti-apoptotic gene in tissue-specific non-malignant stem cells. Here we demonstrate that ABCB5 also serves an anti-apop...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Guo, Q., Berg, G., Wilson, B. J., Gonzalez, G., Ma, J., Gold, J. S., Nandi, B., Huang, Q., Zhan, Q., Murphy, G. F., Waaga-Gasser, A. M., Lian, C. G., Frank, M. H., Gasser, M., Frank, N. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A27: INI1 negative hepatoblastoma, a vanishing entity representing malignant rhabdoid tumor
Conclusion: Based on this finding, morphology is not a robust method of differentiating MRT from SCU-HB. It is possible that many cases previously classified as SCU-HB mainly based on morphology, if retrospectively analyzed for SMARCB1 would be reclassified as MRT.Citation Format: Ladan Fazlollahi, Susan Hsiao, Mahesh Mansukhani, Julia Glade Bender, Andrew Kung, Darrell Yamashiro, Helen Remotti. INI1 negative hepatoblastoma, a vanishing entity representing malignant rhabdoid tumor. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA)...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Fazlollahi, L., Hsiao, S., Mansukhani, M., Bender, J. G., Kung, A., Yamashiro, D., Remotti, H. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B26: Centriole amplification during mammalian multiciliated cell development reveals a novel centrosome asymmetry
The centrosome comprises a mother and a daughter centriole, both regarded as equivalent in their ability to form new centrioles. Their symmetric duplication during the cell cycle is crucial for proper genetic partitioning between the daughter cells. In multiciliated cells, hundreds of centrioles are thought to appear de novo, i.e. independently from the centrosome, to nucleate the same number of motile cilia and propel physiological fluids. The origin of these centrioles remains unknown. Here we provide the cellular mechanism driving large-scale centriole production in multiciliated cells and identify the daughter centriol...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Jord, A. A., Spassky, N., Meunier, A. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA25: Metastatic programs in pancreas cancer
The unusually high metastatic proclivity of pancreas cancer is life-limiting for a majority of patients including those treated at early stages. A minority of patients nevertheless presents with and succumbs to locally destructive disease. These distinct disease presentations and predilections for distant spread versus local growth of the primary tumor also suggest that the appropriate selection and application of systemic versus local therapies might increase their efficacy and prolong patient survival. We have undertaken a systematic effort to dissect the pathophysiologic mechanisms underlying the extreme lethality of pa...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Hingorani, S. R. Tags: Cancer Niche / Cellular Interactions: Oral Presentations - Invited Abstracts Source Type: research

Abstract A25: Role of ABCB5 in progression and therapeutic resistance of glioblastoma
Glioblastoma multiforme (GBM), one of the most lethal human cancers, is the most common and aggressive primary malignant brain tumor. Poor prognosis and high lethality result from tumor recurrence and extreme resistance to chemotherapeutic treatment. Compelling evidence suggests that GBM is a heterogeneous tumor composed of bulk tumor cells as well as of subpopulations of slow-proliferating cancer stem cells with tumor-initiating potential, which evade cell killing and are responsible for tumor recurrence. Current therapeutic strategies are thus aimed at eliminating these refractory tumor subpopulations to alleviate chemor...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Banerjee, P., Berg, G., Wilson, B. J., Guo, Q., Frank, M. H., Frank, N. Y. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B24: Differentiation screen identifies small molecules that target histologically divergent subtypes of patient-derived lung cancer stem cells
Non-small cell lung cancer (NSCLC) is a prevalent and deadly disease because of high incidence and relapse rates. One hypothesis for the high relapse rate is the existence of cancer stem cells (CSCs), a rare subpopulation of cells within these tumors, that are resistant to therapy and thought to be responsible for local and distal recurrence. CSCs are also able to self-renew and differentiate into multiple cell types forming the mass of new tumors. These differentiated progeny that constitute the bulk of the tumor are more sensitive to radiation and chemotherapeutic agents, express tissue of origin markers, and have an int...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Shlyakhter, D., Boucher, D., Gu, Y., Hall, A. B., Krueger, E., Lindquist, A., Murphy, C., Wang, Y., Wood, M., Eustace, B. Tags: Stem Cell of Origin: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A24: The transcriptional regulator JAB1 is a novel regulator of osteosarcoma development
Osteosarcoma is the most common malignant primary bone tumor. Osteosarcoma patients with metastases have a survival rate of only 25%. Therefore, a greater understanding of the pathogenesis of osteosarcoma is needed for better diagnosis and treatment. An emerging player in tumorigenesis is the transcriptional cofactor JAB (also named CSN5, COPS5), through its effects on cell proliferation, differentiation, survival, and cell cycle progression. Our laboratory has recently shown that Jab1 plays critical roles in the successive steps of mouse skeletal development by affecting master developmental regulators Runx2 and Sox9 in a...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Bashur, L., Elliott, R., Zhou, G. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA23: Hippo/YAP signaling in stem cells and cancer
The long-term goals of the Camargo laboratory are to provide basic insight into conserved mechanisms underlying size and growth control. We are particularly interested in the pathways that somatic stem and progenitors cells utilize to sense and respond to growth inputs in vivo. We utilize the mouse as a genetic model to study pathway function and to dissect the mechanisms by which growth control is coordinated. We also employ three-dimensional primary culture, biochemistry, and high-throughpout genetic interrogation in vitro to identify novel growth-control genes and to provide basic molecular mechanisms underlying our in ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Camargo, F. Tags: Signaling Pathways: Hippo/TOR: Oral Presentations - Invited Abstracts Source Type: research

Abstract B23: Epigenetic control of prostate epithelial stem cell differentiation
Introduction: Hormone manipulation offers an effective but short term and time-limited treatment for human prostate cancers, reducing both tumor bulk and serum levels of prostate-specific antigen. In normal prostate, castration results in a loss of luminal cells and persistence of a poorly differentiated basal-like population, which is responsible for repopulation after restoration of hormone levels. However in fetal prostate development, the hormonal stimulus is provided indirectly to the developing epithelial structures via androgen-sensitive stromal cells.To study the drivers of prostate epithelial cell differentiation,...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Maitland, N. J., Packer, J. Tags: Stem Cell of Origin: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA22: Mechanisms of evasive resistance in cancer
Cancer is a major health problem due to the failure of current therapies to effectively eradicate the disease. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, tumors escape such therapies by activating compensatory signaling pathways, a process referred to as ‘evasive resistance’. The identities of the alternative signaling pathways and the functional interconnections that underlie evasive resistance remain widely unknown. Elucidating mechanisms of evasive resistance is currently a major challenge in cancer research. We integrate c...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Dazert, E., Heim, M., Beerenwinkel, N., Hall, M. N. Tags: Signaling Pathways: Hippo/TOR: Oral Presentations - Invited Abstracts Source Type: research

Abstract B22: Analysis of Lgr5-positive cells in mouse mammary gland
Lgr5 has been identified as a stem cell marker in multiple adult tissues, and individual Lgr5+ mammary epithelial cells are capable of regenerating mouse mammary glands in transplantation assays. Here we investigated the proliferation and differentiation capabilities of murine mammary Lgr5+ cells in vitro, and their distribution in mouse mammary glands in vivo. Equal numbers of sorted Lgr5+ and Lgr5- epithelial cells were cultured in Matrigel to evaluate their stem-like properties in vitro. Compared with Lgr5- cells, Lgr5+ cells were more efficient at generating organoids in 3D culture, and the Lgr5+ cell-derived organoids...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Zhang, L., Howe, L., Kolesnick, R., Brown, A. Tags: Stem Cell of Origin: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A22: Differentiation of human embryonic stem cells to sympathetic neurons: A potential model for understanding neuroblastoma pathogenesis
Conclusions: We have established a model of nor-adrenergic SNS development using two hESC lines to improve our understanding of normal human SNS development and in future studies the pathogenesis of neuroblastoma.Citation Format: Jane Carr-Wilkinson, Nilendran Prathalingam, Deepali Pal, Helen Forgham, Majlinda Lako, Mary Herbert, Deborah A. Tweddle. Differentiation of human embryonic stem cells to sympathetic neurons: A potential model for understanding neuroblastoma pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA):...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Carr-Wilkinson, J., Prathalingam, N., Pal, D., Forgham, H., Lako, M., Herbert, M., Tweddle, D. A. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA21: YAP/TAZ biology in development and cancer: Hippo signaling and mechanotransduction
We study how cells sense their environment and use this information to build and maintain tissues with specific form, size and function, and how these systems are corrupted in diseases. At the centerpiece of these events is the activity of the transcriptional coactivators YAP and TAZ. Enhanced YAP/TAZ activity is emerging as a hallmark of multiple human tumors. I will discuss the cell and tissue-level mechanisms that lead to unrestrained YAP/TAZ activity, in turn essential for tumor formation and for tissue regeneration upon injury. I will also present new evidence on the function of YAP/TAZ in regulating the biology of no...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Piccolo, S. Tags: Signaling Pathways: Hippo/TOR: Oral Presentations - Invited Abstracts Source Type: research

Abstract B21: DNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signaling
Emerging evidence suggests that cancer is populated and maintained by tumor initiating cells (TICs) with stem-like properties similar to that of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the DNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7 and thereby enhancing Wnt signaling. Importantly, Fzd7-dependent enhancement of Wnt signaling by DNp63 also governs tumor initiating activit...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Chakrabarti, R., Sinha, S., Kang, Y. Tags: Stem Cell of Origin: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A21: The metastasis-regulator Tenascin C is activated by Wnt/beta-catenin in Ewing sarcoma
A pathogenic role for Wnt/beta-catenin signaling in Ewing sarcoma, an aggressive and highly metastatic tumor characterized by pathognomonic EWS/ETS fusion proteins, has yet to be elucidated. To address the potential importance of Wnt/beta-catenin in Ewing sarcoma we performed immunohistochemical staining of primary tumor specimens and discovered that nuclear beta-catenin is highly heterogeneous, both within and between tumors, and that all tumors with evidence of beta-catenin activation were associated with clinical relapse. These studies led us to hypothesize that activation of Wnt/beta-catenin in Ewing sarcoma cells prom...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Pedersen, E. A., Menon, R., Thomas, D. G., Bailey, K. M., Noord, R. A. V., Chugh, R., Fearon, E. R., Lawlor, E. R. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B20: Key intermediate progenitor in luminal prostate epithelial differentiation dictates susceptibility to Myc overexpression and Pten loss in prostate cancer cell of origin
Conclusions: Prostate cancer oncogenesis requires dysregulation of Myc and Pten, because they are required for the normal PrEC terminal differentiation pathway. Pten loss is required to remove the ING4/Miz1-mediated terminal differentiation program initiated by Myc overexpression, to maintain the intermediate progenitor cells in a partially differentiated, yet proliferative state, and to evade cell death.Citation Format: Penny Berger, McLane Watson, Mary Winn, Cindy K. Miranti. Key intermediate progenitor in luminal prostate epithelial differentiation dictates susceptibility to Myc overexpression and Pten loss in prostate ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Berger, P., Watson, M., Winn, M., Miranti, C. K. Tags: Stem Cell of Origin: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A20: Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL and menin
Ewing sarcoma is driven by the oncogenic fusion protein, EWS-FLI1, and arises via de-regulation of developmental transcriptional programs. Control of normal developmental transcription programs is governed by epigenetic regulation which, in the case of HOX programs, is dependent on coordinated and reciprocal actions of polycomb (PcG) and trithorax (TrxG) proteins. We recently reported that in Ewing sarcoma posterior HOX genes, in particular HOXD13, are abnormally over-expressed and that the promoters of these genes are marked with the TrxG-dependent activating histone modification, H3K4me3. H3K4me3 is deposited by the MLL ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Svoboda, L. K., Bailey, N., Krook, M., Noord, R. V., Harris, A., Patel, R. M., Thomas, D., Cierpicki, T., Grembecka, J., Lawlor, E. R. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A19: Transformation of primary neural crest cells to model pediatric cancers
Neural crest cells (NCCs) are a multipotent, highly migratory cell population specified from the neural tube during embryonic development. NCCs undergo EMT (epithelial to mesenchymal transition) then migrate throughout the body forming diverse lineages including neurons, Schwann cells, melanocytes, and osteoblasts. Precursor cells from NCC lineages are thought to be the cell of origin for several pediatric and adult cancers including neuroblastoma, peripheral primitive neuroectodermal tumors (pPNET), malignant peripheral nerve sheath tumors (MPNST), cranial-facial osteosarcoma, and melanoma.The most common pediatric cancer...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Olsen, R. R., Otero, J. H., Garcia-Lopez, J., Wallace, K. A., Yin, Z., Freeman, K. W. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B18: Strand-specific in vivo screen of cancer-associated miRNAs unveils key drivers and oncogenic targets
MiRNAs are evolutionarily conserved small non-coding RNAs that orchestrate a wide spectrum of physiological and pathological processes in stem cells (SCs) and human cancers. Intimately wired into oncogenic and tumor suppressive networks, miRs are valuable as not only diagnostic biomarkers but also therapeutic targets. Squamous cell carcinomas (SCCs) are among the most life-threatening human cancers world-wide. Using skin as paradigm, we describe the first panoramic view of miRs during the development, homeostasis and malignant transformation of skin epithelium, whose SCs are the target of most common SCCs. Focusing on abun...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Ge, Y., Zhang, L., Nikolova, M., Reva, B., Fuchs, E. Tags: Stem Cell of Origin: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA17: Dynamic changes in the epigenetic landscape during retinal development, cellular reprogramming, and tumorigenesis
The stepwise progression from proliferating multipotent progenitor cells to terminally differentiated neurons in the developing central nervous system (CNS) is marked by dramatic changes in gene expression programs. Those changes in gene expression are accompanied by changes in histone modifications at individual promoters, gene bodies and enhancers as well as changes in the higher order structure of the chromatin. Once established during development, the cell-type specific epigenome of differentiated cells is thought to be relatively stable. Indeed, one of the major barriers to reprogramming differentiated cells such as n...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Dyer, M. Tags: Pediatric Cancers and Development: Oral Presentations - Invited Abstracts Source Type: research

Abstract B17: Traf2- and NCK-interacting kinase (TNIK) inhibitor down-regulates Wnt signaling pathway in cancer cells
Introduction: Aberrant activation of the Wnt signaling pathway has been implicated as the key driver of carcinogenesis, particularly in colorectal cancers. Because nearly 90% of colorectal cancers carry mutations either APC or β-catenin, downstream signaling molecules of the β-catenin destructive complex are considered as more attractive therapeutic targets in drug discovery research for the treatment of colorectal cancers. Recently, Traf2- and NCK-interacting kinase (TNIK) has been identified as one of components of the T-cell factor-4 (TCF4) transcriptional complex and essential for the expression of Wnt target...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Uno, Y., Moriyama, H., Kashimoto, S., Masuda, M., Sawa, M., Yamada, T. Tags: Signaling Pathways: Wnt: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A17: Physical activity and epigenetic age among normative aging study participants
Low levels of physical activity are associated with increased risk and mortality of common cancers including breast and colon, with strong evidence for increasing risk with age. Epigenetic age is a recently developed concept using DNA methylation measurements to describe biological age at the level of human tissues, cells, and organs. Epigenetic age represents deviation from expected DNA methylation patterns associated with chronological age (defined as _age), and is suggested as a possible biological mechanism driving observed associations between physical activity and cancer risk. However, no studies have evaluated assoc...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Hibler, E. A., Zheng, Y., Liu, L., Zhang, W., Penedo, F. J., Phillips, S. M., Conroy, D. E., Schwartz, J., Vokonas, P., Baccarelli, A., Dai, Q., Hou, L. Tags: Epigenetics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA16: SWI/SNF (BAF) complex mutations in cancer
Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in no...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Roberts, C. W. M. Tags: Pediatric Cancers and Development: Oral Presentations - Invited Abstracts Source Type: research

Abstract B16: Potassium channel activators inhibit migration of breast cancer cells by hijacking the WNT signaling pathway
Potassium ion channels are transmembrane associated proteins that play fundamental role in several biological processes including cell proliferation by controlling potassium ion flow across the membrane. Interestingly, the Kv11.1 potassium channel has been found expressed in a large variety of cancers of different histogenesis including breast cancers. However, very little is known about the role of this channels in cancer biology. We recently demonstrated that stimulation of Kv11.1 activity with the pharmacological Kv11.1 activators (e.g. NS1643) induces irreversible growth arrest in several breast cancer cell types, and ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Saverio, G., Rao, V., Perez-Neut, M. Tags: Signaling Pathways: Wnt: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA15: The unique genomic and epigenomic landscape of pediatric high-grade glioma
Diffuse high-grade gliomas (HGGs) of childhood are a spectrum of disease with devastatingly poor outcome. Despite similar histological features, pediatric HGGs arise from a broader distribution of anatomical locations when compared to adults, with approximately 50% arising in the brainstem as diffuse intrinsic pontine glioma (DIPG), a disease found almost exclusively in children. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation as well as developmental signal...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Larson, J. D., Silveira, A. B., Kasper, L. H., Diaz, A. K., Zhu, X., Baker, S. J. Tags: Pediatric Cancers and Development: Oral Presentations - Invited Abstracts Source Type: research

Abstract B15: Transforming growth factor {beta} type III (T{beta}RIII/Betaglycan) suppresses canonical Wnt signaling in ovarian cancer
Ovarian cancer remains the deadliest gynecologic malignancy and the fifth leading cause of death from cancer in women[1]. Transforming growth factor β Type III (TβRIII/Betaglycan) receptor is a ubiquitously expressed co-receptor for the TGF-β ligand superfamily[2] whose expression is significantly decreased or lost in human epithelial ovarian tumors compared to normal tissue, with loss of TβRIII expression correlating with tumor grade and ovarian cancer progression[3]. TβRIII has increasing roles in suppressing cancer progression via cell motility[4], cell adhesion[5], and cell differentiation[2], ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Jenkins, L. M., Varadaraj, A., Flores, H., Karthikeyan, M. Tags: Signaling Pathways: Wnt: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA14: Targeting the Wnt signaling pathway in cancer
Mutations in the adenomatous polyposis coli (APC) gene, resulting in aberrant Wnt pathway activation, were first identified in hereditary and sporadic colorectal cancers in 1991. Today, 24 years later, there are still no approved Wnt pathway inhibitors on the market. In contrast, oncogenic BRAF mutations were discovered in various solid tumors in 2002. Within 9 years the first RAF inhibitor, vemurafenib, received FDA approval for the treatment of BRAF-mutant metastatic melanoma. Why has it been so difficult to develop Wnt pathway inhibitors?The first and most significant challenge has been to identify protein targets withi...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: McLaughlin, M. Tags: Signaling Pathways: Wnt: Oral Presentations - Invited Abstracts Source Type: research

Abstract B14: Wnt signaling circuits in glioblastoma multiforme
Glioblastoma multiforme (GBM) is the most common malignant tumour in the central nervous system with a prevalence of 2-3 cases per 100 000 people. Although the standard treatment of surgery, chemotherapy and radiotherapy improve survival, the median survival continues to remain at only 15 months with a 5-year survival rate of under 10%. Glioma neural stem-like (GNS) cells have been identified in GBM and have the capability of regenerating the tumour. Treatment strategies that target the majority of the tumour may be incapable of also targeting GNS cells and thus characterization of GNS cells may provide insight into additi...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Rajakulendran, N., Selvadurai, H., Rowland, K., Park, N., Batada, N., Dirks, P., Angers, S. Tags: Signaling Pathways: Wnt: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA13: Inhibiting the Wnt pathway with selective anti-Frizzled synthetic antibodies
Secreted Wnt glycoproteins regulate intracellular signaling pathways important for embryonic development and adult tissue homeostasis. Misregulation of Wnt signalling is frequent in human cancers. Wnt ligands are recognized at the surface of cells by various receptor complexes that are differentially expressed and determine context-dependent cellular responses. In humans, 16 Wnt ligands interact directly with 10 Frizzled seven transmembrane proteins through their extracellular cysteine rich domain (CRD). Wnts also interact with various co-receptors, such as LRP5/6, ROR1/2, RYK, PTK7, which engage different downstream signa...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Steinhart, Z., Hart, T., Sidhu, S., Moffat, J., Angers, S. Tags: Signaling Pathways: Wnt: Oral Presentations - Invited Abstracts Source Type: research

Abstract B13: ETC-159 is a novel PORCN inhibitor effective for treatment of Wnt-addicted genetically defined cancers
Pathologic expression of Wnts is found in cancers, fibrosis and other diseases, hence there is considerable interest in blocking Wnt signaling to achieve therapeutic benefit. Post-translational palmitoleation of Wnts at a highly conserved serine residue is essential for their secretion and function. We have pursued a strategy to block all Wnt-dependent pathways concomitantly using a small molecule inhibitor of the enzyme PORCN that is required for Wnt O-palmitoleation. As Wnt pathway inhibitors advance to clinical trials, the paucity of well-defined biomarkers makes it challenging to monitor response to therapeutics.We hav...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Madan, B., Ke, Z., Harmston, N., Petretto, E., Hill, J., Keller, T. H., Lee, M. A., Matter, A., Virshup, D. M. Tags: Signaling Pathways: Wnt: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A13: {beta}2-adrenergic receptor as a potential differentiation marker in prostate cancer
Background and purpose: It has previously been shown that the level of β2-adrenergic receptor (ADRB2) in prostate cancer tissue is correlated with biochemical recurrence (BCR) after radical prostatectomy. Here, we investigated this association in an independent cohort, and utilized stable ADRB2 knockdown in LNCaP cells to identify potential mechanisms.Experimental procedures and results: The protein expression of ADRB2 in prostate cancer tissue from 63 prostate cancer patients (Skåne University Hospital, Malmø, Sweden) was measured by immunohistochemical analysis. Time to BCR was analyzed by Cox regressio...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Ramberg, H., Grytli, H. H., Braadland, P. R., Wang, W., Nielsen, H. K., Krobert, K. A., Levy, F. O., Bjartell, A., Svindland, A., Tasken, K. A. Tags: EMT and Plasticity: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA12: Lgr5 stem cell-based organoids in human disease
The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using lineage tracing experiments in adult mice, we found that these Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that they represent the stem cell of the small intestine and colon. Lgr5 was subsequently found to represent an exquisitely specific and almost ‘generic’ marker for stem cells...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Clevers, H. Tags: Signaling Pathways: Wnt: Oral Presentations - Invited Abstracts Source Type: research

Abstract B12: March E3 ubiquitin ligase is required for head formation by mediating Dishevelled degradation during Xenopus development
Wnt signaling controls numerous biological events including vertebrate development, adult tissue homeostasis and organogenesis. In addition, dysregulation of Wnt itself or its downstream signaling components causes human birth defects and cancer. Dishevelled (Dvl) is a crucial scaffolding protein that exerts activation of Wnt signaling pathway. Recently, several Dvl-interacting proteins have been suggested to mediate the stability of Dvl. However, the molecular mechanisms by which Dvl undergoes degradation remain to be elucidated. Here we identify March, a RING domain-containing ubiquitin ligase, targeting Dvl protein and ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Lee, H., Cheong, S.-M., Han, J.-K. Tags: Signaling Pathways: Wnt: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A12: A retinoblastoma protein phosphorylation code associated with cell adhesion and invasiveness
Lung cancer remains the leading cause of cancer deaths among men and women worldwide. Its five-year survival rate (17.8%) is by far the lowest among the most common cancers such as colon (65.4%), breast (90.5%), and prostate (99.6%). Early detection and screening still remain challenging, and despite the many recent breakthroughs in lung cancer treatment, improvement in the long-term survival of lung cancer patients is still limited. The inactivation of the retinoblastoma tumor suppressor (Rb) is a major driving force behind tumorigenesis in most cancer types, including lung cancer. Rb is a phosphoprotein traditionally kno...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Perez-Morales, J., Gonzalez-Flores, J., Rosa, A. D. L., Estrada, E., Santiago-Cardona, P. Tags: EMT and Plasticity: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA11: C. elegans GLP-1/Notch signaling: Direct targets and visualization in stem cells
My laboratory focuses on the in vivo regulation of stem cell self-renewal and differentiation in the germline tissue of the small nematode C. elegans. In this system, Notch signaling from a single-celled mesenchymal niche promotes maintenance of germline stem cells (GSCs)(1). My talk will focus on two broadly important questions. First, what key downstream effectors of Notch signaling are transcriptionally activated in stem cells to maintain their totipotent state? Second, how does Notch-dependent transcriptional activation maintain a pool of stem cells? We have known for some time that an RNA regulatory network acts downs...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Sorensen, E. B., Lee, C. L., Sorokin, E., Groth, A. C., Kimble, J. Tags: Signaling Pathways: Notch: Oral Presentations - Invited Abstracts Source Type: research

Abstract A11: N-Myc and STAT interactor (NMI): A regulator of developmental signaling and EMT
The NMI protein associates with known key transcription factors such as Myc and STATs and serves as a critical regulatory co-factor that dictates specialized functions. While a physiological function for NMI is yet unknown, it has potential roles in pathologies ranging from viral infection to cancer. We will present pioneering work from our laboratory showing that NMI impacts two major developmental signaling pathways - TGFβ and Wnt pathways.EMT is one of the key phenomena underlying normal embryonic and organ development, with a vital role in metastatic progression. We discovered that the expression of NMI is signifi...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Samant, R. S., Pruitt, H. C., Metge, B. J., Shevde, L. A. Tags: EMT and Plasticity: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA10: Notch signaling and cancer
Cancer can be seen as disease of perturbed self-renewal. In the last decades it became clear that many of the signaling pathways known to be important during embryonic development also play important roles in regulating self-renewing tissues. Deregulation of the self-renewal process results in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis all of which are hallmarks of cancer. The major question is how do these deregulated signaling cascades mechanistically contribute to cancer and are they suitable for targeting therapy?The Notch pathway is one such cascade requir...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Junker, F., Lehal, R., Frimantas, V., Bornhauser, B. C., Bourquin, J.-P., Koch, U., Radtke, F. Tags: Signaling Pathways: Notch: Oral Presentations - Invited Abstracts Source Type: research