bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2814: Effect of kif14 overexpression on tumor formation in mice in a lifespan study
Authors: Pitt Natalie , Sishtla Kamakshi , Shadmand Mehdi , Sulaiman Rania , Sinn Anthony L. , Condon Keith , Sandusky George E. , Corson Timothy W. 
Published: July 2017

Abstract
KIF14 is a mitotic kinesin and microtubule-associated molecular motor that plays an essential role in the last stages of cytokinesis. In multiple cancer types, KIF14, overexpression in tumors correlates with stage, aggressiveness, and poor patient outcomes. There is considerable interest in KIF14 as a possible oncogene, since the KIF14 locus is in a common region of genomic gain in multiple cancers.
In this study, wild type BDF-1 mice and a strain constitutively overexpressing Kif14, known as Kif14-Tg mice, were evaluated at the end of their natural lifespan, specifically for the occurrence of tumors. There were approximately fifty mice per genotype, and eighty of these mice have died. These mice were necropsied and the following tissues were collected: kidney, liver, lung, spleen, seminal vesicles, ovary, mammary gland, bone marrow, pituitary gland, eye, and brain. Any gross nodules were also collected. These tissues were then fixed in 10% neutral buffered formalin, processed, sectioned, and stained with hematoxylin and eosin.
Although there was no significant difference in mouse weights through the lifespan or in the survival curve between the Kif14-Tg and their wild type littermates, a significant increase in follicular lymphoma and diffuse large B cell lymphoma was seen in Kif14-Tg mice compared to the wild type mice. Thirty-three mice developed either a follicular lymphoma or a diffuse large B cell lymphoma, and twenty-four of those mice were Kif14-Tg mice. These were the two most common tumors in Kif14-Tg mice. Other lesions and tumors that were seen in both strains included thymic lymphoma, sarcomas, myeloid dysplasia, and other carcinomas. Nontumorous lesions were seen in both strains of mice including hydronephrosis and telangiectasia in multiple organs. Ballooning degeneration of the lens of the eyes was observed in five mice from the strain Kif14-Tg.
Our finding of increased follicular lymphoma and diffuse large B cell lymphoma proves the first evidence that Kif14 can promote tumor formation in a wild-type background. This is the first evidence that Kif14 may have a role in lymphoma, but complements our earlier finding that Kif14 overexpression can accelerate tumor formation in a mouse model of retinoblastoma. Together, these outcomes further support Kif14’s potential as an oncogene.
Citation Format: Natalie Pitt, Kamakshi Sishtla, Mehdi Shadmand, Rania Sulaiman, Anthony L. Sinn, Keith Condon, George E. Sandusky, Timothy W. Corson. Effect of kif14 overexpression on tumor formation in mice in a lifespan study [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 2814. doi:10.1158/1538-7445.AM2017-2814
Abstract 2818: PDX model of the enriched pleural effusion from advanced lung cancer patient for testing on targeted drug sensitivity and resistance
Authors: Zhang Feifei , Wang Ke , Xu Wenhua , Yang Yang , Ouyang Kedong , Lu Shun , Wen Danyi , Chen Taiping 
Published: July 2017

Abstract
Advanced lung cancer of late stage patients is selectively sensitive to available targeted therapeutics and often developing resistance to the early sensitive drug treatment. Surgery tumor tissues are usually not available to establish patient derived xenograft (PDX) models which is critical to evaluate drug sensitivity and resistance. We applied CD45 magnet beads to enrich the tumor cell population from pleural effusion specimens of advanced lung cancer. Seven PDX models were successfully established in this way. Based on genetic profiling of these models, TKI drug related EGFR mutations and ALK fusion were confirmed (EGFR: L858R, T790M, Exon 19 insertion; ALK fusion). Further in vivo efficacy studies were designed to test on multiple drug sensitivity and resistance including Gefitinib, Erlotinib, Ceritinib, Alectinib, AZD9291. Tumor growth inhibition (TGI) were well matched with corresponding gene mutations among the models. In particularly, T790M model was resistant to Erlotinib and quite sensitive for AZD9291. In conclusion, the models established here are very useful to test on potency of many current investigational TKI drugs and provide base for drug resistant model establishment.
Citation Format: Feifei Zhang, Ke Wang, Wenhua Xu, Yang Yang, Kedong Ouyang, Shun Lu, Danyi Wen, Taiping Chen. PDX model of the enriched pleural effusion from advanced lung cancer patient for testing on targeted drug sensitivity and resistance [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 2818. doi:10.1158/1538-7445.AM2017-2818
Abstract 2819: Intestinal estrogen receptor beta attenuates colon cancer signaling pathways in vivo
Authors: Pettersson Linnea , Saxena Ashish , Vu Trang , Gustafsson Jan-Åke , Archer Amena , Williams Cecilia 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the third most common form of cancer and the second leading cause for cancer deaths. Several epidemiological, in vitro and in vivo studies suggest that Estrogen receptor β (ERβ) could be a possible target for CRC prevention and treatment, but the potential mechanism is not demonstrated. ERβ is expressed in intestinal epithelial cells, as well as in some intestinal immune cells and other tissues. Previous studies have seen increased CRC after full ERβ knockout, but it is not clear if this is mediated by intestinal ERβ. The specific aim of our study is to determine the role of intestinal ERβ during colon cancer development in vivo. We deleted ERβ specifically in the intestine epithelia of mice (iERβKO), and induced CRC using Azoxymethane (AOM) and Dextran Sulfate Sodium (DSS) treatment. After 9 weeks treatment, all mice presented colitis and two iERβKO mice but none of the wild-type (WT) mice had developed tumors. qPCR showed that the expression of pro-inflammatory markers was higher in iERβKO treated mice than in untreated or WT mice, Immunohistochemistry (IHC) of proliferative markers showed that iERβKO exhibited higher cell proliferation in the top of the crypts compared to controls. After 16 weeks treatment, all mice developed tumors. qPCR showed that the expression of mesenchymal markers was higher in treated iERβKO mice compared to treated WT mice. Our results demonstrate that intestinal ERβ attenuates colon cancer-related pathways.
Citation Format: Linnea Pettersson, Ashish Saxena, Trang Vu, Jan-Åke Gustafsson, Amena Archer, Cecilia Williams. Intestinal estrogen receptor beta attenuates colon cancer signaling pathways in vivo [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 2819. doi:10.1158/1538-7445.AM2017-2819
Abstract 2827: Establishing a mouse model to investigate GRB7-mediated signaling in development and triple-negative breast cancer
Authors: Lofgren Kristopher A. , Meier David R. , Cash Steven E. , Kenny Paraic A. 
Published: July 2017

Abstract
Triple-negative breast cancer (TNBC) lacks expression of the estrogen and progesterone steroid receptors and HER2; thus TNBC patients cannot benefit from the recent successes of targeted therapies, and instead rely on cytotoxic chemotherapeutic combinations. As such, tumor recurrence is high and patient prognosis is poor. GRB7 is a cytoplasmic adaptor protein required for cell migration, invasion, and proliferation in TNBC. We have previously reported that a high GRB7 mRNA level was the strongest predictor of tumor recurrence in a cohort of 246 TNBC patients treated with doxorubicin. GRB7 was confirmed in a smaller, independent cohort as an indicator of poor prognosis. After the observation of both decreased doxorubicin sensitivity and elevated GRB7 expression levels in TNBC tumors, we hypothesized that GRB7 was mediating a signaling pathway critical for drug resistance and cell survival.
To determine the role of GRB7 in mouse development and tumorigenesis, the current study focuses on the Grb7tm1a(EUCOMM)Wtsi knockout-first transgenic mouse, in which the insertion of the 1L2_Bact_P cassette upstream of the critical exons of GRB7 renders an effective knockout of GRB7, and the inclusion of loxP sites flanking critical exons of GRB7 facilitates the creation of tissue-specific, conditional GRB7 deletions. Herein, we investigate GRB7 expression in the homozygous Grb7tm1a mouse and derivative tissue-specific deletions, and evaluate their suitability for modeling GRB7-mediated events in mammary gland development and tumorigenesis in a TNBC model. Primary cell lines from the Grb7tm1a mouse and breast cancer cell lines will then be used to delineate the effects of altered GRB7 levels on the mechanism of developmental and TNBC cell signaling, respectively.
Citation Format: Kristopher A. Lofgren, David R. Meier, Steven E. Cash, Paraic A. Kenny. Establishing a mouse model to investigate GRB7-mediated signaling in development and triple-negative breast cancer [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 2827. doi:10.1158/1538-7445.AM2017-2827
Abstract 2829: Identification of transcriptomic signatures of organotropism in pancreatic cancer metastasis
Authors: Zhong Yi , Fan Jun , Huang Jinlong , Iacobuzio-Donahue Christine A. 
Published: July 2017

Abstract
Metastatic disease is the most common cause of death in pancreatic ductal adenocarcinoma (PDA) patients. The most common sites of metastatic spread of PDA are to the liver, lung, and peritoneum. The acquisition of advanced stage PDA tissue samples has greatly improved our descriptive understanding of pancreatic cancer metastasis; however, important aspects of PDA metastatic cell biology remain poorly understood. We have previously shown that distant metastases arise from genetically evolved subclones within the primary site of PDA. To understand the biologic basis of PDA metastatic subclone formation we established a transgenic mouse model of PDA based on heterozygous inactivation of Tgfbr2 in association with p48-Cre mediated activation of mutant Kras and Trp53 alleles (KPTC mice). This model revealed that metastatic efficiency and organotropism are related but independently controlled phenomena by mutant Trp53 gain of function in association with TGFb signaling. Pertubation of TGFb signaling reduced liver but not lung metastasis due to a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma compared to KPC mice. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. To better understand the cell- autonomous features that promote organ specific metastasis, we have established cell lines from primary and metastatic PDAs of KPC mice representing five different target organ sites (liver, lung, peritoneum, omentum, lymph node). RNAseq and WGCNA performed on extracted RNA from these established cell lines indicate gene expression modules that are unique to metastases. Among metastases, gene expression modules have also been identified that are unique to local versus distant metastases. Analyses are ongoing to functionally validate these modules in additional samples of mouse and human PDA. These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically. Identification of cell-autonomous and micro-environmental mechanisms that support PDA organotropism have the potential to reveal novel targets for therapeutic intervention and modulation of the lethal metastatic phenotype.
Citation Format: Yi Zhong, Jun Fan, Jinlong Huang, Christine A. Iacobuzio-Donahue. Identification of transcriptomic signatures of organotropism in pancreatic 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 2829. doi:10.1158/1538-7445.AM2017-2829
Abstract 2835: Potential opposing roles of AKT isoforms in indolent versus aggressive prostate cancer
Authors: Miller Karina A. , Ko Hyun-Kyung , Gelman Irwin H. 
Published: July 2017

Abstract
Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer and the second highest contributor to cancer-related deaths in U.S. men. Localized CaP has a 5-year survival rate of approximately 100%, but disseminated, metastatic disease (mCaP) dramatically reduces 5-year survival to &lt;30%. A known driving force in the progression of CaP is activation of the PI3K/Akt signaling pathway through loss of PTEN, with widespread effects on cell proliferation and migration. Additional genomic changes, such as the loss of TP53 or RB1, or the upregulation of MYC, correlate with increased incidence and aggressiveness of mCaP. However, only a fraction of men with high levels of circulating and disseminated CaP cells progress to overt, macro-metastatic disease - the lethal phenotype in CaP. Importantly, little is known regarding the drivers of indolent vs. aggressive mCaP. We used two transgenic (Tg) mouse models of mCaP with clinically relevant genetic alterations which exhibit Akt activation and Rb1 loss, yet one produces indolent mCaP and the other, systemic aggressive mCaP. Specifically, mice lacking Rb1 and the metastasis-suppressor, SSeCKS/Akap12, develop high-grade prostatic intraepithelial neoplasia (HG-PIN) and disseminated disease in the lymph nodes whereas those lacking Pten and Rb1 develop CaP and aggressive mCaP. The metastasis-suppressing functions of Akap12 relates to its ability to scaffold Src and PKC, thereby attenuating their oncogenic signaling pathways. We will show data suggesting that the pathological differences between these two Tg models is based on the differential use of PI3K-p110 and Akt isoforms, with aggressiveness correlating with the downregulation of Smad4, a known metastasis-suppressor in Tg CaP models. Additionally, differences in Akt isoform usage likely controls the expression of neurogenesis genes that are especially upregulated in castration-recurrent CaP that fails second-line androgen receptor antagonist inhibitors such as enzalutamide. By comparing the differential transcriptomes and signaling networks in primary-site tumors, lymph node metastases, and CaP cell lines derived from these two Tg models, several new potential therapeutic targets have been identified that could be exploited to prevent or treat aggressive mCaP.
Citation Format: Karina A. Miller, Hyun-Kyung Ko, Irwin H. Gelman. Potential opposing roles of AKT isoforms in indolent versus aggressive prostate cancer [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 2835. doi:10.1158/1538-7445.AM2017-2835
Abstract 2839: Systematic enrichment analysis of gene expression profiling studies identifies SPARC dependent consensus pathways implicated in bladder cancer
Authors: John Bincy Anu , Said Neveen 
Published: July 2017

Abstract
Bladder cancer (urothelial cancer of the bladder) is the most common malignancy affecting the urinary system with increasing incidence and mortality. Treatment of bladder cancer has not advanced in the past 30 years. Therefore, there is a crucial unmet need for novel therapies, especially for advanced disease. We have recently reported Secreted Protein Acidic and Rich in Cysteine (SPARC) as a tumor suppressor in urinary bladder cancer that inhibits the multistep cascades on tumor initiation, progression and metastasis. SPARC gene and protein expression was among candidates associated with the tumorigenicity of the isogenic T24/T24t cell lines. We reported that SPARC depletion in human bladder cancer cell lines including T24 cells increased their tumorigenicity and metastatic potential. In addition, SPARC protein and transcript expression are significantly downregulated in advanced urothelial cancer. To gain insight on the molecular mechanisms of the tumor suppressor effects of SPARC in urothelial cancer, we did whole transcriptome profiling of T24 cells depleted of SPARC to identify SPARC-signature associated with bladder cancer invasiveness, progression, and metastasis. Subsequently, we used gene signature enrichment analysis (GSEA) pathway enrichment tools to define functionally related genes that are consistently up- or down- regulated as a function of loss of SPARC. We found that loss of SPARC expression is associated with enrichment of multiple oncogenic signaling pathways that are enriched in muscle invasive urothelial cancer and have been associated with poor prognosis. These pathways include K-ras, Myc-oncogene, p53 pathways as well as DNA damage/repair. Consistent with our earlier reports, loss of SPARC is associated with genes and proteins involved in angiogenesis, inflammation and hypoxia. In addition, we have identified novel signatures involved in unfolded protein response, mTOR signaling, glycolysis and cholesterol metabolism. These comprehensive signatures not only reveal SPARC-dependent networks that cooperate to elicit its biological responses but enables coherent understanding of the etiology of complex bladder cancer disease. Importantly, these signatures identify novel therapeutic opportunities for bladder cancer.
Citation Format: Bincy Anu John, Neveen Said. Systematic enrichment analysis of gene expression profiling studies identifies SPARC dependent consensus pathways implicated in bladder cancer [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 2839. doi:10.1158/1538-7445.AM2017-2839
Abstract 2843: DNMT3B mediated DNA methylation and epigenetic reprogramming of metastatic cancer cells
Authors: So Jae Young , Skrypek Nicolas , Wang Xiang , Merchant Anand , Yang Howard , Chen Wei-Dong , Hu Gangqing , Achyut Bhagelu R , Cam Meggie , Zhao Keji , Lee Maxwell , Yang Li 
Published: July 2017

Abstract
Approximately 90% of cancer patients die from metastasis. In many cases, current therapies are designed based on the primary tumor characterization and are ineffective against metastatic disease. It is not clear whether metastatic cancer cells acquire additional genetic and epigenetic alterations, if so, what are the underlying mechanisms. Using several tumor models, we demonstrated that DNMT3B, de nova DNA methyltransferase, was increased in metastatic nodules in comparison to that from the primary tumors. DNMT3B knockdown or overexpression significantly inhibited or increased metastatic colonization of cancer cells. To understand the underlying molecular mechanisms of DNMT3B regulation, we performed DNMT3B ChIP-seq, RNA-seq, and DNA methylation-seq comparing lung metastases with primary tumors and 4T1 cells. We identified genes that are differentially methylated and expressed. Ingenuity Pathway Analysis revealed DNMT3B targeting multiple oncogenic signaling pathways. Bioinformatics analysis of human databases demonstrated significantly higher expression levels of DNMT3B in metastases than primary tumors in breast, prostate and melanoma cancer patients. In summary, our study demonstrated that DNMT3B as a key epigenetic regulator which plays critical roles for tumor metastasis. Our work suggests DNMT3B as potential therapeutic targets for breast cancer patients with metastatic disease.
Citation Format: Jae Young So, Nicolas Skrypek, Xiang Wang, Anand Merchant, Howard Yang, Wei-Dong Chen, Gangqing Hu, Bhagelu R Achyut, Meggie Cam, Keji Zhao, Maxwell Lee, Li Yang. DNMT3B mediated DNA methylation and epigenetic reprogramming of metastatic cancer cells [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 2843. doi:10.1158/1538-7445.AM2017-2843
Abstract 2845: A Rb phosphorylation code associated with lung cancer metastasis
Authors: Perez-Morales Jaileene , Mejias-Morales Darielys , Torres-Collazo Bryan , Negron-Pagan Harry , Santiago-Cardona Pedro 
Published: July 2017

Abstract
Lung cancer is characterized by its poor prognosis, aggressiveness, and proclivity for early metastasis. Non-small cell lung cancer (NSCLC) it’s the most common type of lung cancer with a five-year survival rate of 18%. Most predictors of metastasis and recurrence of NSCLC rely on post-resection evaluation of tumor histology, which is a severe limitation since only 15% of the patients are diagnosed with resectable disease. Hence, there is a need to characterize biomarkers with metastasis-predicting value in pre-resection small biopsy specimens. In addition to the proclivity for metastasis, another feature of lung cancers is the inactivation of the retinoblastoma protein (Rb). The retinoblastoma protein (Rb) is a tumor suppressor inactivated due to hyper-phosphorylation in most human cancers, including NSCLC. Our preliminary data relates the Rb S249/T821 phosphorylation signature to an epithelial-to-mesenchymal transition (EMT), a trait strongly associated to metastasis. We found that cells that have hyperphosphorylated Rb in residues S249/T821 express EMT markers such as decreased expression of E-cadherin and integrin α5 as well as increased expression of N-cadherin, Vimentin, and p-FAK. We propose to focus on the cell adhesion and migration-related kinase Cdk5 with its activator p39 as the kinase responsible for engendering the Rb S249/T821 phosphorylation signature. Our hypothesis is that Rb phosphorylation in S249 and T821 due to CDK5 activity can have prognostic value by being associated with a metastatic phenotype and EMT. Studies performed in a tissue microarray in a population of NSCLC adenocarcinoma that had undergone EMT found an up-regulation in p39 and that its expression is correlated with metastasis. Knockdown of CDK5 induced a decrease in phosphorylation of Rb S249/T821 with a decrease in E-cadherin expression. These data suggest that CDK5-dependent phosphorylation of Rb can affect cell adhesion by regulating E-cadherin. Introducing p39 into Rb hypo-phosphorylated cell line induced an increase in phosphorylation of Rb residues. Furthermore, the CDK5-p39-Rb axis might point to the explanation and prediction of the metastatic phenotype in lung cancer.
Citation Format: Jaileene Perez-Morales, Darielys Mejias-Morales, Bryan Torres-Collazo, Harry Negron-Pagan, Pedro Santiago-Cardona. A Rb phosphorylation code associated with lung 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 2845. doi:10.1158/1538-7445.AM2017-2845