bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2866: Defining epigenetic vulnerabilities in synovial sarcoma
Authors: Banito Ana , Tasdemir Nilgun , Ladanyi Marc , Lowe Scott W. 
Published: August 2015

Abstract
Synovial sarcoma constitutes 10% of all soft-tissue sarcomas and arises most frequently in adolescents and young adults. The defining genetic event of synovial sarcoma and main driver of the disease is the translocation of the SS18 gene on chromosome 18q11 to either the SSX1 and SSX2 genes located on chromosome Xp11. The resulting SS18-SSX fusion oncogene lacks a DNA binding domain, but is thought to exert its function via interaction with transcription factors and chromatin remodelers such as polycomb-group chromatin remodeling factors, and components of the SWI/SNF complex. The fact that the fusion oncogene is the defining event in this disease suggests that, on its own, it is able to generate an epigenetic profile that drives tumorigenesis.
In this study we expressed SS18-SSX2 in C2C12 myoblasts to recreate the epigenetic events driving synovial sarcoma. C2C12 myoblasts expressing SS18-SSX1/2 did not show significant differences in cell growth however became completely refractory to differentiation to myotubes. In addition, knockdown of SS18-SSX2 in a mouse synovial sarcoma cell line (derived from a mouse model in which the human SS18-SSX2 fusion oncogene is expressed in the myogenic progenitor compartment) led to strong growth arrest and induction of induction of p16 and p21 cell cycle regulators. This results support the notion that the SS18-SSX oncogene drives tumorigenesis by blocking differentiation programs and by repressing tumor suppressor genes to maintain self-renewal of synovial sarcoma cells. To identify epigenetic vulnerabilities that are specifically generated by the SS18-SSX fusion protein we screened two cell lines using an shRNA library targeting epigenetic modulators: the synovial sarcoma cell line mentioned above and C2C12 myoblasts. Three control shRNAs targeting the SS18-SSX2 oncogene were within the top depletion hits in the synovial sarcoma cell line but were neutral in the C2C12 myoblasts, validating the screen performance. To uncover SS18-SSX specific hits we concentrated in genes within this list that specifically depleted in the synovial sarcoma cell line but not in myoblasts. Genes within this list and to which at least two independent shRNAs scored were subjected to extensive one-by one validation. Our results may uncover epigenetic mechanisms required to maintain self-renewal in synovial sarcoma.
Citation Format: Ana Banito, Nilgun Tasdemir, Marc Ladanyi, Scott W. Lowe. Defining epigenetic vulnerabilities in synovial sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2866. doi:10.1158/1538-7445.AM2015-2866
Abstract 2879: Profiling of lung microbial communities in lung cancer and chronic obstructive pulmonary disease patients
Authors: Liu Yanhong , Ajami Nadim J , Wong Matthew C , Scheurer Michael , Amirian E. Susan , Petrosino Joseph F , Spitz Margaret R , Bondy Melissa L , Kheradmand Farrah 
Published: August 2015

Abstract
Background: The composition and structure of site-specific microbiota have recently been described as a biomarker associated with a variety of high impact diseases including cancer. This study sought to identify lung microbial signatures in smokers with lung cancer (LC) and/or chronic obstructive pulmonary disease (COPD).
Material and Methods: We employed 16S rRNA gene compositional analysis to compare the microbiota in Optimal Cutting Temperature (OCT) embedded biopsies of lung-tissue from 30 smokers, including 10 patients with LC only, 10 patients with COPD only, and 10 patients with both LC and COPD, selected from a longitudinal study of COPD exacerbation conducted in Houston, Texas, during 2005 to 2012.
Results: Microbial signatures calculated based on the 16S rRNA gene data showed that patients with COPD only presented a very distinct microbial structure defined by a significantly lower Shannon Diversity Index compared to patients with LC only (P = 0.04), and patients with both LC and COPD (P = 0.003), suggesting lower bacterial richness and evenness. Furthermore, biopsies from patients with COPD only were characterized by an increased prevalence of Acinetobacter (P &lt; 0.0001) and Acidovorax (P &lt; 0.0001), and a lower prevalence of Bifidobacterium, Streptococcus, and Ruminococcus species compared to patients with LC only and those with both LC and COPD. However, patients with both COPD and LC were indistinguishable from those with LC only.
Conclusions: This study is the first and largest to examine the composition of the lung microbiome in smokers with LC and/or COPD. Specific bacterial signatures were identified in patients with LC only and those with both COPD and LC demonstrating that the lung microbiome can be used as a biomarker for the two diseases. Altogether, we observed altered lung microbiota of COPD and LC, but whether this is involved in disease causation or is a consequence of host selection remains unclear.
Citation Format: Yanhong Liu, Nadim J Ajami, Matthew C Wong, Michael Scheurer, E. Susan Amirian, Joseph F Petrosino, Margaret R Spitz, Melissa L Bondy, Farrah Kheradmand. Profiling of lung microbial communities in lung cancer and chronic obstructive pulmonary disease patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2879. doi:10.1158/1538-7445.AM2015-2879
Abstract 288: TG3003, an immunomodulatory anti-CD115 mAb targeting M2-macrophage polarization in the tumor microenvironment
Authors: Haegel Hélène , Ziller-Remy Christelle , Barraud Luc , Bonnefoy Jean-Yves , Cochin Sandrine , Duong Vanessa , Geist Michel , Grellier Benoit , Hallet Rémy , Marchand Jean-Baptiste , Menguy Thierry , Rooke Ronald , Thioudellet Christine , Reymann Carine , Préville Xavier 
Published: August 2015

Abstract
Cancer progression has been associated with the presence of tumor-associated M2-type macrophages (M2-TAMs) able to inhibit anti-tumor immune responses, stimulate neo-angiogenesis and facilitate metastasis. Colony-stimulating factor-1 (CSF-1, M-CSF) is a cytokine required for the survival and differentiation of myeloid cell lineages, and CSF-1 signaling is known to polarize macrophages towards the M2-type. M2-TAMs can represent the most abundant immunosuppressive cell population in the tumor microenvironment, notably recruited by CSF-1 and MCP-1/CCL2.
Transgene has developed a monoclonal antibody (mAb), TG3003, directed against the CSF-1 cell-surface receptor, CD115 (CSF-1R, M-CSFR). This mAb does not block the binding of CSF-1 to its receptor, but down-modulates CD115 signaling. In contrast to other anti-CD115 mAbs currently in development, whose modes of action rely on the blockade of ligand binding, TG3003 is not cytotoxic to normal myeloid cells that require CD115-mediated signaling for their survival. In vitro, TG3003 skews monocyte differentiation from M2-type macrophages towards dendritic cells, most potent antigen-presenting cells capable of stimulating efficacious T cell responses. It inhibits the secretion of MCP-1/CCL2 by differentiating macrophages and decreases their IL-6 production. Through this inhibition of M2-TAMs, TG3003 may potentiate immune responses in patients and impact on tumor progression. Moreover, due to its unique non-competitive mode of action, TG3003 does not block the physiological pathway for CSF-1 clearing from the circulation, thus avoiding the issue of toxic or rebound effects in treated patients.
To investigate the properties of TG3003 in vivo, we have generated a transgenic mouse strain where the mAb epitope has been inserted into murine CD115 without affecting murine CSF-1 binding nor signaling. We will present the results of preclinical proof-of-concept experiments validating the mechanism of action and the immunomodulatory properties of mAb TG3003.
Citation Format: Hélène Haegel, Christelle Ziller-Remy, Luc Barraud, Jean-Yves Bonnefoy, Sandrine Cochin, Vanessa Duong, Michel Geist, Benoit Grellier, Rémy Hallet, Jean-Baptiste Marchand, Thierry Menguy, Ronald Rooke, Christine Thioudellet, Carine Reymann, Xavier Préville. TG3003, an immunomodulatory anti-CD115 mAb targeting M2-macrophage polarization in the tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 288. doi:10.1158/1538-7445.AM2015-288
Abstract 2887: Epigenetic silencing of the DNA repair genes, BRCA1 and MLH1, induced by hypoxic stress in a pathway dependent on the histone demethylase, LSD1
Authors: Lu Yuhong , Chu Adrian , Wajapeyee Narendra , Turker Mitchell S. , Glazer Peter M. 
Published: August 2015

Abstract
Hypoxia is a key microenviromental stress in solid tumors that is associated with poor prognosis. It has been indicated that hypoxia induces genetic instability through multiple mechanisms. Previously, we have shown that BRCA1 and RAD51, in the homology dependent repair (HDR) pathway, and MLH1 and MSH2, key components of MMR, are down-regulated at the transcriptional level in response to hypoxia. Here we show that hypoxia also drives epigenetic modification of the BRCA1 and MLH1 promoters, with decreased H3K4 methylation as a key repressive modification produced by the lysine specific histone demethylase, LSD1. In cells containing the BRCA1 promoter driving a selectable HPRT gene, long-term silencing of the promoter was observed following exposure to hypoxic stress. The silenced clones showed decreased H3K4 methylation and decreased H3K9 acetylation in the BRCA1 promoters, consistent with the acute effects of hypoxic stress. Similarly, we also found that hypoxia causes durable long-term silencing of the MLH1 promoter in a pathway that requires LSD1. Knockdown of LSD1 or its co-repressor, CoREST, also prevents the re-silencing (and associated cytosine DNA methylation) of the endogenous MLH1 promoter in RKO colon cancer cells following transient reactivation by treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC). These results suggest that hypoxia is a driving force for long-term silencing of DNA repair genes, including BRCA1 and MLH1, thereby promoting genome instability and tumor progression.
Citation Format: Yuhong Lu, Adrian Chu, Narendra Wajapeyee, Mitchell S. Turker, Peter M. Glazer. Epigenetic silencing of the DNA repair genes, BRCA1 and MLH1, induced by hypoxic stress in a pathway dependent on the histone demethylase, LSD1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2887. doi:10.1158/1538-7445.AM2015-2887
Abstract 2895: Phosphorylation of EZH2 at T416 by CDK2 promotes development of mammary tumors with basal-like phenotype
Authors: Nie Lei , Wei Yongkun , LaBaff Adam , Yang Cheng-Chieh , Xia Weiya , Huo Longfei , Liu Dongping , Hsu Yi-Hsin , Hortobagyi Gabriel N. , Yao Jun , Kleer Celina G. , Hung Mien-Chie 
Published: August 2015

Abstract
Basal-like breast cancer, also referred to as triple negative breast cancer (TNBC) due to the lack of expression of ErbB2, PR, and ER alpha receptors, is considered to be one of the most aggressive breast cancers, which display high rates of tumor cell proliferation, metastasis, and post-surgical re-occurrence. This subtype of breast cancer presents a major challenge for breast cancer oncologists as currently there is no effective therapy available. Here, we show that Cyclin E and EZH2, the methyltransferase component of the polycomb repressive complex 2 (PRC2) are exclusively co-expressed in TNBC tumor tissues. We further show that CDK2, the only known enzymatic partner of Cyclin E, can phosphorylate EZH2 at T416 in vivo. CDK2-mediated modification of EZH2 at T416 leads to gain-of-function, enhancing its ability to promote breast cancer cell migration/invasion, expansion and self-renewal of tumor sphere in vitro, and tumor growth in vivo. In addition, our immunohistochemistry-staining of 247 primary breast tumor tissues validates that high EZH2/T416 phosphorylation correlates with poor survival in TNBC but not in non-TNBC patients. To further attest the oncogenic role of EZH2/T416 phosphorylation by CDK2 in vivo, we generated transgenic mice expressing EZH2T416D mutant, a mimicking phosphorylated form of EZH2, in mammary glands. In contrast to previously reported EZH2WT transgenic mice, which did not develop mammary tumors, our EZH2T416D-expressing mice developed malignant mammary tumor with basal-like and highly metastatic potential phenotypes. These genetic evidence revealed that CDK2/Cyclin E mediated site-specific phosphorylation of EZH2 is capable of inducing the basal-like/TNBC phenotype and maintaining cancer stem cell population of breast cancers so that the T416 phosphorylation of EZH2 might serve as a biomarker for TNBC prognosis and effective therapy.
Citation Format: Lei Nie, Yongkun Wei, Adam LaBaff, Cheng-Chieh Yang, Weiya Xia, Longfei Huo, Dongping Liu, Yi-Hsin Hsu, Gabriel N. Hortobagyi, Jun Yao, Celina G. Kleer, Mien-Chie Hung. Phosphorylation of EZH2 at T416 by CDK2 promotes development of mammary tumors with basal-like phenotype. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2895. doi:10.1158/1538-7445.AM2015-2895
Abstract 2903: Differential regulation of LC3 A and B, GABARAPL 1 and 2 autophagy genes by micro-environmental stress and role in breast cancer survival
Authors: Zois Christos E. , Haider Syed , Wigfield Simon , Giatromanolaki Alexandra , Sivridis Efthimios , Morten Karl , Roxanis Ioannis , Leek Russell , Buffa Francesca , Koukourakis Michael , Harris Adrian L. 
Published: August 2015

Abstract
The microtubule-associated protein light chain 3 MAP1LC3 (LC3) and GABARAPL1 and 2 are the major proteins to monitor autophagy. Here, we analyzed the role of both MAP1LC3, GABARAPL1 and 2 in breast cancer cells and primary human breast cancer. HER2 amplified (BT474, SKBR3, MDA-MB-453), ER positive (MCF7, T47D) and triple negative (MDAMB231) breast cancer cell lines were studied in response to hypoxia, in high [25mM] and low glucose [5mM] treatment. Low glucose increased the basal levels for LC3A-II, LC3B-II and GABARAPL2-II in BT474, MCF7 and MDAMB231 cell lines. SKBR3 cell line had the lowest autophagic protein levels for LC3B-II, and Gabarapl2-II and was the most resistance to the autophagy inhibition mediated using siRNAs to all theseIn hypoxia both LC3B (up to 8 fold) and GABARAPL1 (up to 12 fold) mRNA expression were induced in all cell lines (p&lt;0.001). MAP1LC3A knockdown significantly decrease cell proliferation in BT474, MCF7 and MDAMB231 while GABARAPL2 knockdown additionally decreased baseline cell proliferation in T47D and SKBR3 breast cancer cells (p&lt;0.05, n = 3). Moreover, using the Seahorse, decreased MAP1LC3A and GABARAPL2 expression by siRNA led to cellular bioenergetic changes including increased basal oxygen consumption of the MCF7.
Co-expression analysis of autophagic genes define distinctive clusters of MAP1LC3, GABARAPL 1 and 2 with the hypoxic signature in breast cancer subtypes using the METABRIC series.
The expression levels of the MAP1LC3 and GABARAPL1 and 2 among the breast cancer subtypes and normal tissue showed significant suppession of all of them in cancer compared to normal breast tissue. In conclusion, all the pathways were suppressed at RNA level in cancer compared to normal, baseline levels were not associated with core classification of breast cancer types. These latter data were confirmed in a breast cancer cell line panel, which showed a marked variation in inducibility by environemntal stress and role in survival under low glucose and hypoxia. Thus analysis of induced gene expression in response to stress may be important, or heterogeneity in selection of tumors for anti-autophagy therapy.
Citation Format: Christos E. Zois, Syed Haider, Simon Wigfield, Alexandra Giatromanolaki, Efthimios Sivridis, Karl Morten, Ioannis Roxanis, Russell Leek, Francesca Buffa, Michael Koukourakis, Adrian L. Harris. Differential regulation of LC3 A and B, GABARAPL 1 and 2 autophagy genes by micro-environmental stress and role in breast cancer survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2903. doi:10.1158/1538-7445.AM2015-2903
Abstract 2910: The dual role of autophagy in cadmium induced prostate carcinogenesis
Authors: Das Trinath P. , John Arokya MS , Suman Suman , Ankem Murali , Damodaran Chendil 
Published: August 2015

Abstract
Cadmium chloride (Cd) and cadmium products cause both acute and chronic cytotoxicity and Cd exposure correlates with the risk of cancer, especially prostate cancer in humans. On the cellular and molecular level, Cd compounds may promote transformation of healthy cells to a malignant state by inducing expression of pro-survival signaling molecules. However, the precise molecular mechanism by which Cd affects cellular transformation in different tissue types, especially in prostate, is yet to be delineated. Autophagy is an intracellular lysosomal degradation process by which cells remove damaged organelles and maintain the integrity of intracellular components. In cancer cells, autophagy promotes cancer cell survival as well as cell death. It is unclear of how, and under what circumstances, these dual and opposite roles of autophagy affect both anti-oncogenic and oncogenic functions. It is possible that uncharacterized molecular switch that influences the anti-oncogenic function of autophagy in healthy cells to become oncogenic.
In our studies, we found that exposure of normal prostate epithelial cells (RWPE-2) in culture to Cd (10μM) results in growth inhibition. By contrast, the growth of Cd-transformed prostate epithelial (CTPE) cells was not inhibited by the same Cd treatment. While analyzing the molecular link between Cd induced toxicity and generation of reactive oxygen species (ROS) generation in RWPE-2 and CTPE cells; we found there was no significant change in the ROS induction in both cell types. In addition, no changes in the expression of autophagy targeted genes (Atg family proteins) were seen in Cd treated in both non-transformed and transformed cells. However, microtubule-associated protein 1A/1B-light chain 3B (LC-3B), which is directly involved in autophagy initiation was upregulated in Cd-treated non-transformed cells, but not in Cd-treated transformed cells. LC-3B activation also correlated with growth inhibition in non-transformed cells, while impairing LC-3B activation in RWPE-2 cells causes resistance to CD induced growth inhibition. Our ongoing study will determine whether induction of autophagy via LC-3B is a key event that facilitates Cd-mediated conversion of non-transformed prostate epithelial cells to a malignant state. We strongly believe our studies will define a new concept of LC-3B mediated autophagy in Cd-induced prostate carcinogenesis.
Citation Format: Trinath P. Das, Arokya MS John, Suman Suman, Murali Ankem, Chendil Damodaran. The dual role of autophagy in cadmium induced prostate carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2910. doi:10.1158/1538-7445.AM2015-2910
Abstract 2911: Leptin Notch VEGFR-2 axis influences cancer stromal cell behavior
Authors: Lanier Viola , Jeffers Merle , Walterberger Johannes , Anderson Leonard , Gonzalez Ruben 
Published: August 2015

Abstract
PURPOSE: Breast cancer cells induce changes in the stromal environment during malignancy. These changes promote growth, angiogenesis, invasion, and metastasis. The secretion of the adipokine, leptin, from adipose tissue has been shown to contribute to cell proliferation, migration and survival. We previously reported that leptin induces Notch, a pro-survival factor and contributor to the VEGF/VEGFR-2 pro-angiogenic system. We hypothesize that the leptin Notch axis induces activation of fibroblast cells and leads to endothelial cell proliferation, tubule formation, and survival.
These effects could be related to leptin-induced Notch expression and VEGFR-2 transactivation, independent of VEGF.
METHODS: Mouse Embryo Fibroblast cells (NIH/3T3), human umbilical vein endothelial cells (HUVEC) and porcine aorta endothelial cells (PAEC) were challenged with leptin (dose and time-response), and inhibitors of Notch (DAPT) and VEGFR-2 (SU5416 kinase inhibitor). Expression of Notch, VEGFR-2, Ob-R and phosphorylation of VEGFR-2 were determined. The impact of treatment on angiogenic features of endothelial cells was determined. To determine whether leptin-Notch axis activates fibroblast cells, leptin doses 0.6, 1.2, and 6.2 were used. RESULTS: Leptin induced phosphorylation of VEGFR-2 at intracellular site Y1175 and tubule formation in HUVEC. Leptin induced phosphorylation of VEGFR-2 at sites Y951, Y996, Y1059, and Y1175 in PAEC VEGFR2. Protein expression of Notch4 and Jagged1 was induced by leptin treatment in NIH/3t3 cells.
CONCLUSION: Leptin secreted by fibroblast cells and/or adipose tissue may contribute to tumor angiogenesis by acting directly on stromal cells and inducing a VEGFR-2/Notch crosstalk. Novel therapies that target leptin signaling could be a new strategy for the prevention and treatment of breast cancer. These therapies could be more relevant for obese cancer patients with high circulating amounts of leptin.
Citation Format: Viola Lanier, Merle Jeffers, Johannes Walterberger, Leonard Anderson, Ruben Gonzalez. Leptin Notch VEGFR-2 axis influences cancer stromal cell behavior. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2911. doi:10.1158/1538-7445.AM2015-2911