bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4789: A novel MIF signaling pathway drives the malignant character of pancreatic cancer by targeting NR3C2
Authors: Yang Shouhui , He Peijun , Wang Liming , Wang Jian , Schetter Aaron , Tang Wei , Funamizu Naotake , Yanaga Katsuhiko , Uwagawa Tadashi , Satoskar Abhay R. , Gaedcke Jochen , Bernhardt Markus , Ghadimi B. Michael , Gaida Matthias M , Bergmann Frank , Werner Jens , Ried Thomas , Hanna Nader , Alexander H. Richard , Hussain S. Perwez 
Published: July 2017

Abstract
Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally, and clinically characterized using cell lines, a genetically engineered mouse model, and PDAC patient cohorts. Here, we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof of principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management.
Citation Format: Shouhui Yang, Peijun He, Liming Wang, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Katsuhiko Yanaga, Tadashi Uwagawa, Abhay R. Satoskar, Jochen Gaedcke, Markus Bernhardt, B. Michael Ghadimi, Matthias M Gaida, Frank Bergmann, Jens Werner, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain. A novel MIF signaling pathway drives the malignant character of pancreatic cancer by targeting NR3C2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4789. doi:10.1158/1538-7445.AM2017-4789
Abstract 4808: Effect of Merkel cell polyomavirus large and small T-antigen on the thrombospondin and the periostin promoter
Authors: Konstantinell Aelita , Furuholmen Ida Sofie , Sveinbjørnsson Baldur , Moens Ugo 
Published: July 2017

Abstract
Merkel cell carcinoma (MCC) is a rare, but aggressive form of skin cancer with rising incidence and high mortality rate. Approximately 80% of MCC tumors are positive for Merkel cell polyomavirus (MCPyV), suggesting a causative relationship between MCPyV and MCC. Exosomes are 30-150 nm vesicles that contain proteins, lipids, mRNAs, lncRNAs, and miRNAs. Exosomes from virus-infected cells comprise also viral nucleic sequences and proteins. Because tumor cell-derived exosomes may contribute to cancer, we hypothesized that MCPyV may affect the composition of exosomes and play a role in tumorigenesis. Therefore, we compared the proteins in exosomes produced by MCPyV-positive MKL1 and MKL2 and MCPyV-negative MCC13 and MCC26 MCC cell lines.
Our proteomic analysis of exosomes originating from polyomavirus-negative and polyomavirus-positive MCC cell lines revealed the presence of the oncogenic proteins periostin and thrombospondin. Western blot analysis of exosomes and lysates of these MCC cells confirmed the presence of these proteins in exosomes from all cell lines. Thrombospondin, but not periostin was detectable in cell lysates, and an enrichment of both proteins was detected in exosomes of all cell lines. The effect of MCPyV large T-antigen (LT-ag) and small t-antigen (st-ag) on the periostin and thrombospondin promoters was examined by transient transfection studies with luciferase reporter plasmids. Transfection experiments in MCC13 revealed that LT-ag, but not st-ag significantly increased the activity of the thrombospondin and periostin promoters. In MCC26 cells, neither LT-ag nor st-ag had a significant effect on the thrombospondin promoter activity, while both proteins alone or in combination significantly stimulated the periostin promoter strength. Our results suggest that MCPyV proteins may contribute to tumorigenesis by enhancing the expression of the oncoproteins thrombospondin and periostin and promote their secretion via exosomes.
Citation Format: Aelita Konstantinell, Ida Sofie Furuholmen, Baldur Sveinbjørnsson, Ugo Moens. Effect of Merkel cell polyomavirus large and small T-antigen on the thrombospondin and the periostin promoter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4808. doi:10.1158/1538-7445.AM2017-4808
Abstract 4834: 3D modeling of immune cell interactions in breast cancer and prediction of immunotherapy response
Authors: Guo Qi , Shuford Stephen , McKinley Brian , Rippon Mary , Cornett Wendy , O'Rourke Mark , Schammel David , Edenfield Jeff , Kaplan David L. , Crosswell Hal E. , Desrochers Teresa 
Published: July 2017

Abstract
While breast cancer has an overall 5-year survival rate of 89%, the rate for patients with stage 4 metastatic disease is only 26%. Immunotherapies have the potential to improve the prognosis for these patients while also providing better treatment options for all breast cancer patients since they have fewer side effects enabling longer treatment times and the use of combination therapies and reduced chances of developing resistance. Currently these treatments are tested in standard 2D cell cultures that are inaccurate in mimicking in vivo drug response or animal models where the immune system differs from humans in numerous ways including T-cell subsets, cytokine receptors, and costimulatory molecule expression. We have developed 3D models of human breast cancer that span the subtypes, ER+, HER2+, and triple negative, incorporate numerous stromal cell types, fibroblasts and adipocytes, and include different immune cells, macrophages and T-cells under either static or perfusion culture systems. These models have been used to examine how tumor cells influence macrophage differentiation using undifferentiated peripheral blood mononuclear cells (PBMCs), how M1 and M2 macrophages influence tumor cell survival and proliferation, how the combination of these cell types influence cytokine secretion, and how the microenvironment affects macrophage invasion. We have also used these complex models to examine response of tumor cells and T-cells to checkpoint inhibitors through standard viability assays and flow cytometry. These models have several potential uses which include the ability to quickly answer whether a particular immunotherapy agent is effective for that particular patient-specific manner and to screen potential novel immunotherapeutic candidates and/or combinations prior to clinical use.
Citation Format: Qi Guo, Stephen Shuford, Brian McKinley, Mary Rippon, Wendy Cornett, Mark O'Rourke, David Schammel, Jeff Edenfield, David L. Kaplan, Hal E. Crosswell, Teresa Desrochers. 3D modeling of immune cell interactions in breast cancer and prediction of immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4834. doi:10.1158/1538-7445.AM2017-4834
Abstract 4847: NME1 mediates a switch in beta integrin subunits that correlates with prolonged patient survival
Authors: Leonard M. Kathryn , Snow Grace , Novak Marián , McCorkle Joseph R. , Yang Xiuwei H. , Belkin Alexey , Kaetzel David M. 
Published: July 2017

Abstract
Expression of the metastasis suppressor NME1 in melanoma is associated with reduced cellular motility, invasion, and metastasis, but the molecular mechanisms underlying this activity are not completely understood. Herein we report a novel mechanism through which NME1 modulates focal adhesion dynamics via regulation of integrins β1 and β3. Stable expression of NME1 significantly altered focal adhesion turnover at the cell periphery. Interestingly, over-expression of NME1 resulted in a switch from predominantly fast recycling α4β1 integrins to slower recycling αvβ3 integrins. Contrary to its regulation of other cell surface receptors, the inhibition of integrin β1 and induction of integrin β3 by NME1 was found to occur at the transcriptional level rather than through dynamin mediated endocytosis. Induction of integrin β3 required both the 3-5’ exonuclease and nucleoside diphosphate kinase (NDPK) activities of NME1, which are also required for its metastasis suppressor activities in vivo. Further suggesting that the induction of integrin β3 is involved in the metastasis suppression function of NME1, knockdown of integrin β3 significantly increased the invasion capability of cells expressing NME1 in vitro compared to control cells. Analysis of metastatic melanoma patients in the TCGA showed individuals with a 1.5x or greater increase in integrin β3 mRNA had a significantly longer overall survival times. Additionally, an inverse correlation was observed between NME1 and integrin β1 mRNA in an independent microarray of primary melanomas. The inverse correlation of NME1 and integrin β1 RNA was also a strong predictor of prolonged distant disease free and overall survival in patients with the basal-like subtype of breast carcinoma. Together, these data strongly suggest NME1 prevents metastasis of human melanoma and some types of breast cancers by altering beta integrin expression to reduce recycling of focal adhesions and, ultimately suppress of cell motility.
Citation Format: M. Kathryn Leonard, Grace Snow, Marián Novak, Joseph R. McCorkle, Xiuwei H. Yang, Alexey Belkin, David M. Kaetzel. NME1 mediates a switch in beta integrin subunits that correlates with prolonged patient survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4847. doi:10.1158/1538-7445.AM2017-4847
Abstract 4854: Evaluating HDAC6 as a causal factor in metastatic breast cancer to develop immunotherapy
Authors: Banik Debarati , Hadley Melissa , Kim Jennifer , Knox Tessa , Nair Jayakumar , Kozikowski Alan , Shen Sida , Vyas Charu , Donohue Ashleyn , Sotomayor Eduardo , Villagra Alejandro 
Published: July 2017

Abstract
Histone deacetylases (HDACs), originally described as histone modifiers, have recently been demonstrated to modify a variety of other proteins involved in diverse cellular processes unrelated to the chromatin environment, including the modulation of proteins related to cell cycle/apoptosis and immune regulation. In contrast to the well-documented effects of HDAC inhibitors (HDACi) in the control of cell cycle and apoptosis, their role in immune-biology is incompletely understood. We have found that the pharmacological or genetic abrogation of a single HDAC, i.e. HDAC6, inactivates the STAT3 pathway and modulates the expression of immuno-regulatory proteins, including the down-regulation of PD-L1, PD-L2 and B7-H4, important negative regulators of immune function, often over-expressed in cancer cells; including breast cancer. HDAC6 has been also involved in a number of structural functions related to cellular motility, shape and intracellular transport through the regulation of the acetylation of numerous targets, including tubulin and cortactin. This function is strongly suggestive of HDAC6 being a key player in metastatic cancer progression. In our initial studies we observed that the selective HDAC6 inhibitor Nexturastat A is capable of reducing the tumor growth in a highly aggressive murine mammary carcinoma that mimics human triple negative breast cancer (TNBC), under both orthotopic and subcutaneous conditions of implantation. Additionally, we observed that the size and number of secondary tumor nodules in lungs were significantly diminished after the HDAC6i treatment. In order to boost the anti-tumor T-cell response, we also tested check-point inhibitors against the tumor (such as anti PD-1 and CTLA4 antibodies). While each of the standalone treatments showed a certain degree of success in reducing tumor growth and enhancing intra-tumoral IFNγ, we demonstrated that HDAC6i improves anti-tumor immune responses when combined with immune check-point blockade.
Citation Format: Debarati Banik, Melissa Hadley, Jennifer Kim, Tessa Knox, Jayakumar Nair, Alan Kozikowski, Sida Shen, Charu Vyas, Ashleyn Donohue, Eduardo Sotomayor, Alejandro Villagra. Evaluating HDAC6 as a causal factor in metastatic breast cancer to develop immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4854. doi:10.1158/1538-7445.AM2017-4854
Abstract 4857: TAK1 mediated IL1 expression as autocrine signaling to promote breast cancer metastasis
Authors: Iriondo Oihana , Elhodaky Mostafa , Liu Yarong , Lee Grace , Lang Julie E. , Wang Pin , Yu Min 
Published: July 2017

Abstract
TGFβ-activated kinase 1 (TAK1), a serine/threonine kinase from the MAPKKK family, is regulated by different cytokines such as IL1, TGFβ, TNFα and BMPs, and it is therefore a key player in the cellular responses induced by changes in the microenvironment. TAK1 regulates cell survival, differentiation and inflammatory responses by activating other intracellular kinases such as p38, JNK or IKK. TAK1 activation is thought to influence the progression of several types of cancer, including lymphomas and pancreatic, colon, liver and breast cancer. In this study, we aimed to investigate the mechanisms by which TAK1 regulates breast cancer progression. (5Z)-7-Oxozeanol is a compound that inhibits the kinase activity of TAK1. Treatment of mice injected with MDA-MB-231 cells with (5Z)-7-Oxozeanol containing nanoparticles reduced metastasis formation, while growth of the primary tumor was not affected. TAK1 involvement in metastasis was confirmed by xenotransplantation experiments done with MDA-MB-231 cells overexpressing wild type or dominant negative forms of TAK1. Using these stable cell lines, we confirmed that TAK1 is required for p38 activation induced by several cytokines. Interestingly, cells cocultured with macrophages showed a TAK1-dependent increase in the expression levels of IL1α and IL1β, which can lead to TAK1 activation themselves. These cytokines were also detected in cancer cells that colonized the mouse lung, suggesting that the lung microenvironment could promote the initiation of a positive feedback loop by cancer cells, promoting the growth of metastatic lesions. Disruption of this positive autocrine feedback loop may be a potential therapeutic approach to suppress breast cancer metastasis to the lung.
Citation Format: Oihana Iriondo, Mostafa Elhodaky, Yarong Liu, Grace Lee, Julie E. Lang, Pin Wang, Min Yu. TAK1 mediated IL1 expression as autocrine signaling to promote breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4857. doi:10.1158/1538-7445.AM2017-4857
Abstract 4861: The role of PRAME in promoting uveal melanoma metastasis
Authors: Sanchez Margaret I. , Field Matthew G. , Kuznetsov Jeffim N. , Kurtenbach Stefan , Pham Dien , Harbour James W. 
Published: July 2017

Abstract
Uveal melanoma (UM) is the most common primary eye cancer and has a predisposition for fatal metastasis. Our group has shown that UMs can be categorized by gene expression profiling (GEP) into two molecular classes associated with metastatic risk: Class 1 (low metastatic risk) and Class 2 (high metastatic risk). While the majority of Class 2 UMs (71%) metastasize, only 38% of Class 1 UMs metastasize. Our group was the first to identify the cancer-testis antigen PRAME as a biomarker for increased metastatic risk in Class 1 UMs, and sub-categorized these tumors into Class1 PRAME+ (intermediate metastatic risk) and Class1 PRAME- (low metastatic risk) subgroups. Further we identified PRAME+ was associated with shorter time to metastasis and worse prognosis in class 2 patients. We have now shown that this PRAME expression is correlated with hypomethylation in the promoter region of the gene, suggesting a mechanism for its expression. Since we have previously shown that PRAME is associated with early metastasis in Class 1 and Class 2 UMs, we hypothesized that PRAME plays a direct role in UM metastasis. To better understand the role of PRAME in UM, we used Class1PRAME+ (F41) and Class1PRAME– (Mel290) UM cell lines to develop in vitro models to study the role of PRAME. Since F41 cells are PRAME+ and highly metastatic, we constitutively silenced PRAME with a V5 tag (F41 shPRAME-V5). For Mel290 cells, we overexpressed PRAME to see whether this cell line, which does not induce metastatic death, became more malignant. We confirmed the silencing and overexpression of PRAME in our transformed cells with western blot. For cell proliferation, we found a slight increase in the Mel290 PRAME+ cells compared to non-transformed Mel290. Strikingly, in F41 cells, knockdown of PRAME led to complete cell death. In a xenograft animal model, NSG male mice were injected with either Mel290 PRAME-V5, Mel290, F41 shPRAME-V5 or F41 TET-empty vector cells. We found that PRAME overexpressing cell lines (Mel290 PRAME-V5 and F41 TET-empty vector) induced rapid, multiple and aggressive liver metastases that led to death, whereas the non-expressing PRAME cells (Mel290 and F41 shPRAME-V5) did not present macro or micrometastasis in any cases. This data highly suggests that PRAME overexpression is involved in UM metastasis. Thus, PRAME mRNA expression is not only a prognostic biomarker but also could be an important target for treatment.
Citation Format: Margaret I. Sanchez, Matthew G. Field, Jeffim N. Kuznetsov, Stefan Kurtenbach, Dien Pham, James W. Harbour. The role of PRAME in promoting uveal melanoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4861. doi:10.1158/1538-7445.AM2017-4861
Abstract 4866: CD47 promotes metastasis and proliferation of colorectal cancer via MAPK/ERK pathway
Authors: Hu Tuo , Chen Yu-feng , Zhou Chi , Ke Jia , Liu Hua-shan , Zheng Xiao-bin , Wang Jian-ping , Wu Xiao-jian , Wu Xian-rui , Lan Ping 
Published: July 2017

Abstract
Background and Aim: A number of studies demonstrated that CD47 was overexpressed in several kinds of tumors including colorectal cancer (CRC). Furthermore, the level of CD47 was positively correlated with tumor proliferation, stemness and metastasis. The aim of this study is to evaluate the role of CD47 in the metastasis and proliferation in CRC.
Methods: We used the data from GEO database GSE8671 to analyze the expression level of CD47 and its relationship with prognosis in CRC. The expression levels of CD47 in normal and CRC tissues from our hospital were detected using quantitative RT-PCR and western blot. CD47 was downregulated or overexpressed via lentiviral vector system. Then the RTCA assay and migration assay were carried out to investigate the function of CD47 in cell proliferation and migration. Western blot for cancer related pathways was performed to find out the downstream signaling pathways of CD47.
Results: Increased expression of CD47 was found in CRC tissues. Inhibition of CD47 expression in HCT116 by ShRNA attenuated the capacity of cell proliferation and migration. On the other hand, overexpression of CD47 in DLD1 increased the capacity for cell proliferation and migration. CD47 induced cell proliferation and migration was found to be associated with the activation of MAPK/ERK pathway.
Conclusions: High expression of CD47 was found to be associated with the proliferation and metastasis in CRC via the activation of MAPK/ERK signaling pathway. These findings provide an SIRPα-independent mechanism for CD47 in the progression of CRC, which may find a novel therapy target for the precise treatment of CRC.
Citation Format: Tuo Hu, Yu-feng Chen, Chi Zhou, Jia Ke, Hua-shan Liu, Xiao-bin Zheng, Jian-ping Wang, Xiao-jian Wu, Xian-rui Wu, Ping Lan. CD47 promotes metastasis and proliferation of colorectal cancer via MAPK/ERK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4866. doi:10.1158/1538-7445.AM2017-4866
Abstract 4868: RD3 reprogramming in N-MYC non-amplified neuroblastoma evolution
Authors: Somasundaram Dinesh Babu , Subramanian Karthikeyan , Aravindan Sheeja , Herman Terence , Natarajan Aravindan 
Published: July 2017

Abstract
N-MYC amplification is restricted to ~30% of the high-risk neuroblastoma (NB), while the remaining 70% is N-MYC non-amplified (N-MYC-NA), yet still has a poor outcome with only 37% 5 Year OS and a miserable 9% 10Y OS. Recently, we demonstrated, Retinal Degeneration Protein 3 (RD3) regulates metastatic state of NB cells and its loss associates with poor prognosis. Herein, utilizing bed-to-bench approach coupled with in vitro, in vivo and ex vivo NB models, we investigated the role of RD3 reprogramming in the evolution of N-MYC-NA-NB. Assessing 15 different human derived stage-4 N-MYC-NA-NB cell lines demonstrated: transcriptional/translational loss of RD3 compared to neural crest cells; cell specific loss and; association of RD3 loss to cellular progressive disease, cellular therapy resistance and disease relapse. Further, in silico analysis demonstrated that RD3-loss was intrinsically associated with reduced OS and abridged relapse-free survival in N-MYC-NA-NB patient cohorts. We also demonstrated the complete loss of RD3 in metastatic site-derived aggressive cells (regardless of CSC status) ex vivo and in reproducible aggressive disease models in vivo. RD3-loss correlated with the heightened metastatic state (tumor cell migration, invasion and tumorosphere formation) of the N-MYC-NA-NB cells. Further, re-expressing RD3 in aggressive cells reverted their metastatic potential both in vitro and in vivo. These results demonstrate the loss of RD3 in high-risk N-MYC-NA-NB, its novel tumor evolution stabilization function and further imply that continuous ongoing acquisition of RD3-loss in therapy resistant cells may directly relate to tumor progression and poor clinical outcomes.
Citation Format: Dinesh Babu Somasundaram, Karthikeyan Subramanian, Sheeja Aravindan, Terence Herman, Aravindan Natarajan. RD3 reprogramming in N-MYC non-amplified neuroblastoma evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4868. doi:10.1158/1538-7445.AM2017-4868