bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2034: Traf2-and Nck-interacting kinase (TNIK) inhibitor, NCB-0846, suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer
Authors: Sugano Teppei , Masuda Mari , Uno Yuko , Goto Naoko , Seike Masahiro , Sawa Masaaki , Gemma Akihiko , Yamada Tesshi 
Published: August 2018

Abstract
Epithelial mesenchymal transition (EMT) has been implicated in cancer cell migration, invasion, and metastasis. Transforming growth factor-β (TGF-β) signal was known to be an essential EMT promotor. Development of therapeutics for targeting EMT through the TGF-β signal may be beneficial for the management of cancer metastasis. Recently, we found that a Traf2- and Nck-interacting kinase (TNIK) inhibitor, named NCB-0846, was capable of attenuating tumor-initiating cells among human colorectal cancer (1, 2). The cross link between EMT and cancer stemness has been revealed in several studies. Therefore we evaluated whether this small-molecule compound could have efficacy to inhibit TGF-β-induced EMT. NCB-0846 reduced the expression of mesenchymal markers (Vimentin and N-cadherin) and upregulated the expression of epithelial marker E-cadherin in A549 and H2228 cells. NCB-0846 suppressed the phosphorylation and nuclear translocation of Smad proteins and also inhibited migration, invasion, and metastasis. NCB-0846 inhibited TGF-β1-induced EMT through the down-regulation of TGFBR1 in mRNA levels. MiR-186-5p and miR-320 family were identified as candidate miRNAs that could target TGFBR1 and inhibited TGFBR1 protein expression.NCB-0846 might be a novel therapeutics drugs that targets the invasion and metastasis through inhibiting TGF-β-induced EMT in lung cancer.
1. Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacology & therapeutics. 2015;156:1-9. Epub 2015/11/07.2. Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, et al. TNIK inhibition abrogates colorectal cancer stemness. Nature communications. 2016;7:12586. Epub 2016/08/27.
Citation Format: Teppei Sugano, Mari Masuda, Yuko Uno, Naoko Goto, Masahiro Seike, Masaaki Sawa, Akihiko Gemma, Tesshi Yamada. Traf2-and Nck-interacting kinase (TNIK) inhibitor, NCB-0846, suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2034.
Abstract 2046: Structural analysis of VEGFR2 function blocking antibodies
Authors: Wary Anita 
Published: August 2018

Abstract
The vascular endothelial growth factor receptor-2 (VEGFR2) is a receptor tyrosine kinase that is expressed highly in endothelial cells (ECs). By binding to VEGF165 (VEGF-A) VEGFR2 signals in ECs mediate the formation of new blood vessels, a process known as angiogenesis. Growth of tumor and metastasis depends on angiogenic activities of ECs. Thus, an agent that blocks VEGFR2 signaling specifically in tumor ECs could inhibit tumor growth and metastasis. The IMC-1121B is an antiangiogenic agent that inhibits the VEGFR2 signaling. Here we modeled the structure of the 1121B Fab fragment in complex with domain-3 of VEGFR2, and the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain-3. The two Fab fragments interact at opposite ends of VEGFR2 domain-3; 1121B blocks VEGF binding, whereas 6.64 appears to prevent receptor dimerization by perturbing the domain-3:domain-4 interface. Blocking of VEGFR2 signaling activities by two different antibodies could be a powerful approach to block angiogenesis, thereby inhibiting growth of tumor and metastasis.
Key reference: Franklin MC et al., Structure 2011;19:1097-1107.
Citation Format: Anita Wary. Structural analysis of VEGFR2 function blocking antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2046.
Abstract 2056: CPAP promotes angiogenesis via interacting with and enhancing the activity of STAT3 in HCC
Authors: Chen Ruo Yu 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) is one of the malignant hypervascular tumors in which angiogenesis plays a vital role in tumor growth and metastasis. Our previous studies indicated that CPAP is overexpressed in HCC, and is positively correlated with recurrence and vascular invasion. In this study, we demonstrated that overexpressed CPAP increases tumor growth, angiogenesis, as well as metastasis ex vivo and in vivo. The expression level of CPAP has a positive correlation with activated STAT3 in HCC. Mechanistically, CPAP can act as a transcriptional co-activator of STAT3 to enhance IL-6-induced STAT3 activation by directly binding with STAT3. Overexpressed CPAP up-regulates several target gene expressions of STAT3 that are involved in angiogenesis, such as IL-8, CD44 and MCAM. The expression of CPAP mRNA is positively correlated with the levels of IL-8, CD44 and MCAM mRNAs in HCC. Importantly, IL-6/STAT3-mediated angiogenesis is significantly increased by overexpressed CPAP, and can be blocked by decreased expression of IL-8. Taken together, our results suggest that overexpressed CPAP interacts with STAT3 to enhance its activity and therefore leads to angiogenesis. Our findings shed light on the importance of CPAP to act as a potential therapeutic target in inhibiting the angiogenesis pathway.
Citation Format: Ruo Yu Chen. CPAP promotes angiogenesis via interacting with and enhancing the activity of STAT3 in HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2056.
Abstract 2060: The pseudogene FLT1P1 functions as a tumor metastasis suppressor in a preclinical model of colorectal cancer
Authors: Ye Xiangcang , Fan Fan , Bhattacharya Rajat , Boulbes Delphine R. , Wang Rui , Xia Ling , Ellis Lee M. 
Published: August 2018

Abstract
Chromosome 3p21.3 is one of the unstable genomic loci that are frequently altered by epigenetic modifications or interstitial deletions in human solid tumors. Several genes in 3p21.3 are known to be tumor suppressors. This locus includes a non-coding gene, fms-related tyrosine kinase 1 pseudogene 1 (FLT1P1), of which the role is largely unknown. Our previous published study (Ye et al. MCR, 2015) found that FLT1P1 was transcribed primarily as an antisense that inhibits VEGFR1 protein expression through interaction with miR-520a in human colorectal cancer (CRC) cells. In this study, we showed that the expression of FLT1P1 antisense is silenced by promoter hyper-methylation in xenograft tumors. Our data further showed that the loss of the FLT1P1 antisense not only up-regulated the expression of VEGFR1 and other genes relating to tumor angiogenesis, but also induced the EMT phenotype in tumor cells. Moreover, the FLT1P1 silenced cells demonstrated an increase in the number of metastasis to the liver following spleen injection in a mouse model. These observations suggest that the transcribed FLT1P1 antisense is a tumor metastasis suppressor. Our finding warrants further investigation of the genetic and epigenetic alterations of FLT1P1 and their impact on metastasis of CRC cells.
Citation Format: Xiangcang Ye, Fan Fan, Rajat Bhattacharya, Delphine R. Boulbes, Rui Wang, Ling Xia, Lee M. Ellis. The pseudogene FLT1P1 functions as a tumor metastasis suppressor in a preclinical model of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2060.
Abstract 2062: Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry
Authors: Durbin Adam D. , Zimmerman Mark W. , Dharia Neekesh V. , Abraham Brian J. , Abraham Brian J. , Balboni-Iniguez Amanda , Weichert-Leahey Nina , He Shuning , Krill-Burger John M. , Root David E. , Vazquez Francisca , Tsherniak Aviad , Hahn William C. , Golub Todd R. , Young Richard A. , Look A. Thomas , Stegmaier Kimberly 
Published: August 2018

Abstract
Childhood neuroblastomas with MYCN gene amplification form a particularly high-risk subset of this disease and are difficult to treat effectively. This has focused attention on tumor-specific gene dependencies that reflect important pathways in tumorigenesis, and thus could provide valuable targets for the development of novel therapeutics. Using genome-scale CRISPR-Cas9 approaches that allow unbiased detection of genes critically involved in tumor cell growth and survival, we identified 147 candidate genes associated with selective vulnerabilities in nine MYCN-amplified neuroblastoma cell lines, compared to findings in over 300 other human cancer cell lines representing multiple tumor cell types. We then used genome-wide ChIP-seq analysis to test the hypothesis that a small number of transcription factors - MYCN, HAND2, ISL1, PHOX2B, GATA3, and TBX2, all represented in the selective dependency group - are members of the transcriptional core regulatory circuitry (CRC) that underlies cell state in MYCN-amplified neuroblastoma. We show that these transcription factors bind as dense clusters at defined epicentres within the enhancers of their own genes, as well as those of the other CRC transcription factor genes, creating a positive feed-forward autoregulatory loop that establishes and maintains high levels of gene expression. To disable the CRC, we tested a combination of BRD4 and CDK7 inhibitors, which we postulated would act synergistically by targeting both transcriptional initiation and elongation required to synthesize regulatory transcription factors. MYCN-amplified neuroblastoma cells treated with both drugs were killed synergistically, in vitro and in vivo, and accompanied by rapid downregulation of CRC transcription factor gene expression. This study defines a set of critical dependency genes in MYCN-amplified neuroblastoma, a subset of which comprises the oncogenic transcriptional regulatory circuitry that underlies cell state and survival in this tumor.
Citation Format: Adam D. Durbin, Mark W. Zimmerman, Neekesh V. Dharia, Brian J. Abraham, Brian J. Abraham, Amanda Balboni-Iniguez, Nina Weichert-Leahey, Shuning He, John M. Krill-Burger, David E. Root, Francisca Vazquez, Aviad Tsherniak, William C. Hahn, Todd R. Golub, Richard A. Young, A. Thomas Look, Kimberly Stegmaier. Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2062.
Abstract 2063: SAMD9/SAMD9L mutations in familial monosomy 7
Authors: Bryant Victoria , Wong Jasmine , Schwartz Jason , Lamprecht Tamara , Ma Jing , Mullighan Charles , Loh Mignon , Shannon Kevin , Klco Jeffery 
Published: August 2018

Abstract
The purpose of this study was to define the mutations causing familial monosomy 7 with myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). We have previously reported frequent germline mutations in the genes SAMD9 and SAMD9L in pediatric MDS. We obtained samples on 32 individuals in 7 families with multiple siblings affected with MDS/AML and monosomy 7. We conducted targeted sequencing of genes frequently mutated in MDS/AML and amplicon sequencing of SAMD9 and SAMD9L. We performed cell cycle analysis assays on SAMD9/9L mutations to study their effects on cell proliferation. Our data show that 5 of the 7 families have germline pathologic mutations in SAMD9 (n=1) and SAMD9L (n=4), with significant clinical variability in the phenotypes displayed, ranging from transient monosomy 7 to overt AML with monosomy 7. Consistent with previous data, the mutant SAMD9 or SAMD9L allele was underrepresented in the bone marrow. This decrease in the mutant allele paralleled the extent of monosomy 7, suggesting that only the wild-type allele was retained in cells with monosomy 7. Functional analysis revealed that all germline SAMD9/9L mutations displayed a gain-of-function ability to suppress cell cycle progression. The patients with more aggressive disease were found to harbor somatic mutations in SETBP1, ETV6 or RUNX1. In many individuals we found additional somatic revertant mutations in cis with the germline mutation, which overcame the growth-suppressive effects of the germline mutation. Our data show that germline mutations in SAMD9/9L represent a new class of predisposition genes for familial monosomy 7 with MDS/AML and should be screened for in all children with MDS.
Citation Format: Victoria Bryant, Jasmine Wong, Jason Schwartz, Tamara Lamprecht, Jing Ma, Charles Mullighan, Mignon Loh, Kevin Shannon, Jeffery Klco. SAMD9/SAMD9L mutations in familial monosomy 7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2063.
Abstract 2074: Single-cell RNA-seq reveals heterogeneity for stem cell markers, LRG5 and CD271 to predict a subpopulation in Ewing sarcoma cells with lower levels of BRAF
Authors: Khoogar Roxane , Houghton Peter 
Published: August 2018

Abstract
Introduction: Ewing Sarcoma (ES) is an aggressive bone and soft tissue tumor, which has a high rate of recurrence among all childhood cancers. This suggests the need for a better understanding of heterogeneous cancer populations. In many cancers, recurrence and therapy resistance has been suggested to be due to the relative state of quiescent cells. Our previous work has shown that low EWSR1-FLI1 expressing cells have a significantly lower proliferative activity, which is similar to a quiescent state. Therefore, we used cells with low EWSR1-FLI1 expression to model and predict cells with a quiescent state.Methods: Using siEWSR1 to suppress EWSR1-FLI1, we studied proliferative quiescence. The Fluidigm C1 system was used to perform SMART-Seq whole transcriptome amplification using EW8 cells. We sequenced single- cell RNA-Seq libraries prepared from 700 ES cells. We developed a computational analysis to profile single cells. Then, we used gene expression signatures derived from the quiescent population to classify parental cells with ensemble classifiers. Results: Results revealed that EW8 cells show considerable heterogeneity at the transcriptome level in control (scrambled RNAi) as well as in the quiescent populations. We identified a subpopulation of EW8 cells with a negative correlation between the expression of LGR5 and Nerve Growth Factor Receptor (NGFR/CD271). Our preliminary data from 255 single cells indicate that LGR5 (0-43.57 TPM, median 0) and CD271 (0-80.05 unique transcripts, median 6.33) were correlated (r= -0.12, P&lt;0.0001) in EW8 cells. CD271 is a surface membrane protein, and a mesenchymal stem cell marker, that regulates stemness, and heterogeneity. A subpopulation of cells with low CD271 was distinguished and studied for its co-expression pattern with LRG5 and BRAF. Conclusions: Our results suggest that there are multiple subpopulations within EW8 parental (Control) cells. We can characterize them with proliferation, stemness, motility and dormancy-associated markers. Ongoing studies are aimed to determine, if EW8 cells having elevated LGR5 exhibit different sensitivity to cytotoxic agents. Data derived from this work are expected to provide insights into the extent to which CD271 contributes to dormancy, and ES heterogeneity. Whether CD271 regulates proliferation to promote a dormant state in this subpopulation is being studied.
Citation Format: Roxane Khoogar, Peter Houghton. Single-cell RNA-seq reveals heterogeneity for stem cell markers, LRG5 and CD271 to predict a subpopulation in Ewing sarcoma cells with lower levels of BRAF [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2074.
Abstract 2102: UFH-001: A novel triple-negative, CAIX-positive cell line for small-molecule targeting of human breast cancer
Authors: Mboge Mam Y. , Chen Zhijuan , Ai Lingbao , Tu Chingkuang , Carta Fabrizio , Supuran Claudiu , Frost Christopher J. , Zhang Zaihui , McKenna Robert , Heldermon Coy , Frost Susan C. 
Published: August 2018

Abstract
Specific treatment options for patients with metastatic breast cancers, especially of the triple negative subtype (TNBC), are limited and most patients develop resistance to radiation and/or chemotherapy. Because of this, the mortality rate in women with TNBC remains high. Carbonic anhydrases (CAs), most specifically membrane-bound CAIX, has been shown to play an important role in tumor progression and as a result is validated as a therapeutic target in several aggressive cancers. In breast cancer, CAIX expression has been shown to be ubiquitous in hypoxic TNBC tissues and is considered a prognostic marker and a potential therapeutic target. Therefore targeting CAIX activity, using small molecule inhibitors, in these highly aggressive and metastatic TNBCs may serve to improve overall disease free survival and therapeutic outcome in clinics. Our goal for this study was to 1) Identify and/or develop a cell line that expresses CAIX in a hypoxia independent manner and is representative of TNBCs and 2) To target CAIX activity in this cell line and observe the effects of CAIX inhibition on its growth and metastasis. Our hypothesis is that CAIX inhibition, in the context of a hypoxic and/or acidic microenvironment, will dysregulate its ability to maintain the acidic pH preferred by cancer cells which favors their growth and migration. To achieve our aims, we newly developed and characterized an endogenous CAIX-expressing cell line named UFH-001. Our results show that CAIX expression and activity in this cell line, although endogenous under normoxic conditions, is increased more than 2 fold under hypoxic conditions. This cell line is also representative of TNBCs (ER/PR and HER2 negative) with a more epithelial-like morphology and phenotype. UFH-001 cells grow aggressively and have the ability to migrate/invade and form tumors in vivo. In these studies we have also shown how inhibition of CAIX activity, using sulfonamide-based inhibitors, affects UFH-001 growth in an apoptosis independent manner and decrease the migratory/inhibitory capacity of these cells. Taken together, our observations indicate that CAIX is a viable small molecular drug target for the treatment of patients with TNBCs.
Citation Format: Mam Y. Mboge, Zhijuan Chen, Lingbao Ai, Chingkuang Tu, Fabrizio Carta, Claudiu Supuran, Christopher J. Frost, Zaihui Zhang, Robert McKenna, Coy Heldermon, Susan C. Frost. UFH-001: A novel triple-negative, CAIX-positive cell line for small-molecule targeting of human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2102.
Abstract 2114: 3D co-culture of pancreatic tumor sphroids and stellate cells using minipillar array as a microtumor model of pancreatic ductal adenocarcinoma
Authors: Hwang Hyun Ju , Oh Min-Suk , Kim Seul-Ki , Kuh Hyo-Jeong 
Published: August 2018

Abstract
Purpose: Tumor microenvironmental (TME) factors play important roles in cancer progression and chemoresistance by inducing epithelial-mesenchymal transition (EMT) and related mechanisms. Pancreatic stellate cell (PSC) is a highly-enriched cell type in TME of pancreatic ductal adenocarcinoma (PDAC). Three dimensional (3D) tumor spheroids (TS) are considered as an in vivo-like tumor model demonstrating its clinical relevancy. We previously developed a minipillar array histochip for 3D culture and immunohistological analysis of TS in an increased throughput manner. Here, we present a minipillar-based co-culture of TS and PSC as a novel in vitro microtumor model of pancreatic ductal adenocarcinoma. Methods: Minipillar chips were obtained from MBD Co. (Cellvitro™ 55Cryo). 3D TS of Panc-1, human PDAC cells and PSCs (Sciencell) were cultured on minipillars and at the bottom of 96 well plates, respectively, as embedded in type I collagen. Changes in expression of extracellular matrix (ECM) and EMT-related factors in TS were assessed by confocal microscopy following cyrosection preparation. Results: Co-culture condition was optimized for the growth of TS, activation of PSC, and their interaction. Expression of EMT markers such as TGF-β1 and vimentin increased in co-cultured TS than mono-cultured TS. ECM remodeling as indicated by increased matrix deposition (collagen I, fibronectin) and fiber organization was observed in TS co-cultured with PSC compared to mono-cultured TS. Upon drug exposure (gemcitabine and paclitaxel), survival advantage was prominent in TS co-cultured with activated PSC. Conclusions: We established 3D model of PDAC by co-culturing TS and PSC using minipillar histochips. EMT-related changes including ECM remodeling and drug resistance were recapitulated in the model. Overall our results indicate usefulness of the present model not only in studying the role of TME factors and their interactions towards tumor progression but also in the evaluation of therapeutic efficacy of drug candidates and combinations.
Citation Format: Hyun Ju Hwang, Min-Suk Oh, Seul-Ki Kim, Hyo-Jeong Kuh. 3D co-culture of pancreatic tumor sphroids and stellate cells using minipillar array as a microtumor model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2114.
Abstract 2119: Bone Morphogenetic Protein Receptor 1a in myeloid cells regulates mouse prostate cancer growth
Authors: Straign Desiree M. , Novitskiy Sergey V. , Owens Philip 
Published: August 2018

Abstract
The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has mirrored the complex roles in diverse contexts during cancer development. BMP signaling is rarely mutated and can be frequently overexpressed in many human cancers. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Myeloid cells including macrophages and neutrophils have been shown to be tumor promoting when stimulated from BMP signaling. We discovered that conditional deletion of BMPR1a in myeloid cells (LysM-Cre) would affect tumor progression and found smaller tumors in a syngeneic FVBn prostate cancer model. Specific changes occurred in myeloid cells both in tumor-bearing mice and non-tumor naïve mice throughout multiple tissues. We profiled myeloid subsets both in the bone marrow, spleen and primary tumor. We found that BMPR1a loss in myeloid cells altered the differentiation and lineage capability of distinct populations by histologic, flow cytometry and high-dimensional mass cytometry analysis. These results indicate a distinct genetic requirement for BMP signaling in myeloid cells during tumor progression.
Citation Format: Desiree M. Straign, Sergey V. Novitskiy, Philip Owens. Bone Morphogenetic Protein Receptor 1a in myeloid cells regulates mouse prostate cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2119.