bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4589: SRC drives invasion of luminal, but not basal, bladder cancer
Authors: Wehrenberg Bryan , Ochoa Andrea , Choi Woonyoung , McConkey David 
Published: August 2019

Abstract
Preventing progression from non-muscle invasive to muscle invasive bladder cancer (BC) is a major clinical priority. This transition is defined by tumor invasion through the bladder epithelium basement membrane into the lamina propria and muscle wall. Inhibition of SRC, a pro-invasion, non-receptor tyrosine kinase that signals as part of a complex with Focal Adhesion Kinase (FAK), may prevent BC progression. We hypothesize that SRC inhibition will disrupt migration and invasion of BC cells. Using The Cancer Genome Atlas (TCGA) mRNA expression data of human bladder tumors, we generated a classifier to subtype tumors as either “luminal” or “basal” and compared SRC expression between the groups. We then sequenced a panel of 30 bladder cancer cell lines. Each cell line was given a subtype call based on our luminal- basal classifier, and levels of SRC mRNA expression were examined. To determine the impact of SRC inhibition on luminal and basal subtypes, we exposed BC cell lines to the SRC-Family Kinase inhibitor, AZD0530. The impact of SRC inhibition on proliferation was measured by MTT assay. Transwell assays were used to examine the effect of SRC inhibition on migration, collagen invasion, and Matrigel invasion. Phosphorylation of SRC downstream targets after AZD0530 treatment was assessed by western blot. The role of SRC target and signaling partner FAK in migration was determined by siRNA knockdown and transwell assay. Luminal human bladder tumors had significantly greater SRC mRNA expression than basal tumors (p&lt;0.001). SRC expression was also enriched in luminal BC cell lines (p&lt;0.05). Inhibiting SRC with AZD0530 had minimal impact on proliferation with no subtype specific effects. Migration and collagen invasion of all luminal cell lines was significantly reduced by AZD0530 treatment (p&lt;0.05). The majority of luminal models capable of invading Matrigel were also inhibited by AZD0530. In contrast, invasion and migration of the majority of basal cell lines was not significantly reduced by SRC inhibition, and was significantly increased in several cases (p&lt;0.05). Both luminal and basal models exhibited reduced phosphorylation of SRC downstream targets when exposed with AZD0530. siRNA knockdown of FAK had no impact on migration in a basal cell line. Enrichment of SRC expression in luminal tumors and significant reductions in luminal cell line invasion after AZD0530 treatment suggest SRC promotes invasion in luminal BC. These results suggest AZD0530, and other SRC-Family Kinase inhibitors, could serve as effective anti-progression agents in luminal BC.
Citation Format: Bryan Wehrenberg, Andrea Ochoa, Woonyoung Choi, David McConkey. SRC drives invasion of luminal, but not basal, bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4589.
Abstract 4591: Overexpression of p62/IMP2 can promote cell migration in hepatocellular carcinoma (HCC) via activating Wnt/ β-catenin pathway
Authors: Xing Mengtao , Shi Jianxiang , Li Pei , Qin Jiejie , Zhang Xiaojun , Ma Yangcheng , Wang Xiao , Francia Giulio , Zhang Jianying 
Published: August 2019

Abstract
There are three members in the family of insulin-like growth factor 2 mRNA binding proteins (IMP): IMP1, IMP2 and IMP3. The IMPs are oncofetal proteins, expressed during embryogenesis and lost in most tissues in adults. However, IMPs were found overexpressed in various cancers. IMPs share similar protein structure in mammals and have similar functions: to bind specific mRNAs, regulate their expression, transportation, and degradation. Although p62/IMP2 was first reported as a tumor-associated antigen in HCC around 20 years ago, we still know little about the role of p62/IMP2 in HCC progression. Our previous studies found that p62/IMP2 was not only overexpressed in HCC tissues, but also overexpressed in HCC cell lines. To explore the biological roles of p62/IMP2 in HCC progression, p62/IMP2 was knockout in two p62/IMP2 positive HCC cell lines (SNU449, HepG2). Due to the low expression level of p62/IMP2 in SNU449, we performed the transfection experiment to overexpress p62/IMP2 in this cell line. The Wound healing assay and transwell migration assay indicated that overexpressed p62/IMP2 in both cell lines showed the ability that could promote the cell migration significantly (p&lt;0.05). On the contrary, the lack of p62/IMP2 expression can reduce the cell migration ability (P&lt;0.05). After analyzing the HCC expression data from Gene Expression Omnibus (GEO), the high and low IMP2 expression groups were set up based on the median expression of p62/IMP2 from GSE 14520. Three genes were selected in differential gene expression analysis with a cancer-metastasis related gene profile, including CTNNB1, ACTR2, VASP (LogFC &gt; 0.3, Adj. p&lt;0.001). Then we performed a western blotting analysis to explore the effect of overexpressed p62/IMP2 on Wnt/β-catenin pathway-related proteins. Overexpressed p62/IMP2 significantly enhance the expression of Wnt and β-catenin, whereas inhibiting the expression of Gsk3b and E-cadherin. Moreover, the migration ability of SNU449 and HepG2 cells were significantly reduced (p&lt;0.05) after cultured with 10mM Wnt/β-catenin signaling pathway inhibitor XAV939 for 24h. In summary, our data showed that overexpressed p62/IMP2 can enhance the migration ability of HCC cells via activating Wnt/β-catenin signaling pathway.
Citation Format: Mengtao Xing, Jianxiang Shi, Pei Li, Jiejie Qin, Xiaojun Zhang, Yangcheng Ma, Xiao Wang, Giulio Francia, Jianying Zhang. Overexpression of p62/IMP2 can promote cell migration in hepatocellular carcinoma (HCC) via activating Wnt/ β-catenin pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4591.
Abstract 4592: CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis
Authors: Chen Joanne Jeou-Yuan , Guo Jing-You 
Published: August 2019

Abstract
Cell surface receptor CD44, an important player in stem cells and cancer biology, is expressed in multiple isoforms via alternative splicing. CD44 isoforms containing variant exon 6 (CD44v6)-encoded sequences are frequently overexpressed in human tumors. In many cancers, CD44v6 serves as a marker of cancer stem cells and accounts for the metastatic susceptibility of the tumors. CD44v6 predicts for poor prognosis in several cancers. However, the actions and underlying mechanisms related to CD44v6-mediated malignant phenotypes remain to be established. In this study, we performed cDNA microarray and Gene Set Enrichment Analysis (GSEA) of the genome-wide expression profiles in cells ectopically expressing the standard form CD44 (CD44s) or CD44v6, and showed that pathways related to cell migration, invasion and metastasis are enriched in CD44v6-expressing cells which are in contrast to cell growth regulatory pathways identified in CD44s cells. In support, overexpression of CD44v6 promoted cell migration and invasion. In silico analyses of genes preferentially regulated in CD44v6-expressing cells against a multi-cancer metastasis-associated gene expression signature dataset and the gene set indicative of embryonic stem cell identity, Collagen XIA1 (COL11A1) was identified as the top candidate in CD44v6-upregulated genes. COL11A1, encoding the α1 chain of the minor fibrillar collagen XI, has been found to be highly expressed in a variety of cancers, and is implicated in the processes of metastasis, angiogenesis, and drug resistance. COL11A1 expression is correlated with cancer aggressiveness and progression, and lymph node metastasis. Using gain- and loss-of-function approaches, we further demonstrated that CD44v6 drives tumor cell invasion in part mediated through the induction of metastasis-related gene COL11A1. Upon examining the involvement of receptor tyrosine kinase pathways, we showed that EGFR is constitutively activated in CD44v6-expressing cells, and that COL11A1 supports CD44v6-mediated EGFR activation via suppressing the expression of PTPRG, an EGFR negative regulator. Our data thus suggest that CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis.
Citation Format: Joanne Jeou-Yuan Chen, Jing-You Guo. CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4592.
Abstract 4599: PD-1/PD-L1 axis in cancer cells contributes to cellular EMT in lung adenocarcinoma
Authors: Su Wen-Pin , Chang Li-Chan , Yan Jing-Jou , Su Wu-Chou 
Published: August 2019

Abstract
Background: Since intrinsic PD-1 receptor functions promote tumor growth was reported, we will investigate the role of PD-L1 in lung adenocarcinoma cells, and their impact on clinical outcome.
Materials and methods: Lung adenocarcinoma CL1-5 cells, derived from CL1-0 cells have more invasive ability. We prepared PDL1-overexpression human lung adenocarcinoma cell line, derived from CL1-0 cells (CL1-0-PD1) and from PC14PE6 cells (PC14PE6-PD-L1). We observed the cellular morphology, and invasiveness; epithelial-mesenchymal transition (EMT) markers and regulators were also evaluated. To explore interaction between PD-1 and PD-L1, we treated the CL1-0, CL1-5, CL1-0-PDL1 cells, PC14PE6 cells, and PC14PE6-PD-L1 cells with anti-PD-1 antibody, and then evaluated cellular invasion. We also suppressed PD-1 to test whether PD-1/PDL-1 interaction contributed to the EMT change. Further, we evaluated cellular proliferation and chemosensitivity by MTT assay and colony formation assay. Finally, we correlated PD-L1 expression with clinical outcome in patients’ tumor specimen.
Results: CL1-5 cells possessed higher PD-L1 expression than parental CL1-0 cells. CL1-0 cells with PD-L1 overexpression had more expression of EMT regulators and mesenchymal markers. Overexpression of PD-L1 in another lung adenocarcinoma PC14PE cells (PC14PE6-PD-L1 cells) become more aggressive. On the contrary, down-regulation of PD-L1 in CL1-5 cells and PC14-PE6-PD-L1 cells became indolent. Besides through the observation from confocal microscopy, PD-L1 expression was more co-localized with vimentin and slug, individually in CL1-5, CL1-0-PD-L1 and PC14PE6-PD-L1 cells. Therefore, PD-L1 promoted EMT in human lung adenocarcinoma cells. After adding anti-PD-1 antibody in CL1-5, CL1-0, and CL1-0-PDL1 cells, migration and invasion ability were decreased. Similar phenomenon was found when PD-1 antibody treatment in PC14PE6 cells, and PC14PE6-PD-L1 cells. Silencing PD-1 by siRNA also disrupt the cellular aggressivenss in CL1-0-PD-L1 and PC14PE6-PD-L1 cells. These results indicated PD-1/PD-L1 axis regulated cancer cells migration and invasiveness. PD-L1 expression also decreased cellular proliferation and had little influence on chemsensitivity. Finally, we found that higher PD-L1 expression was correlated with lymph node metastasis in clinical specimen.
Conclusion: Lung adenocarcinoma cells with higher PD-L1 expression promote EMT via PD-1 receptor. PD-L1 expression lowers proliferation rate, but has little impact on chemosensitivity. Lung cancer patients with high PD-L1 expression in tumor have higher lymph node metastasis.
Citation Format: Wen-Pin Su, Li-Chan Chang, Jing-Jou Yan, Wu-Chou Su. PD-1/PD-L1 axis in cancer cells contributes to cellular EMT in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4599.
Abstract 4603: To analyse PIMT function in glioblastoma cell invasion
Authors: Belkourchia Fatima , Desrosiers Richard 
Published: August 2019

Abstract
The protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT) is an enzyme able to repair abnormal L-aspartyl residues in damaged proteins. Among examined tissues, PIMT shows the highest level in brain. U87-MG cells are a commonly used grade IV cellular model to study the most frequent brain tumor, the glioblastoma. Previously, we reported that PIMT amount increased when U87-MG cells were detached from the extracellular matrix. Recently, our laboratory also showed that PIMT possessed pro-angiogenic properties. Together, these PIMT features led us to postulate that PIMT could play a critical role in glioblastoma growth. To investigate PIMT involvement during glioblastoma growth, we analyzed its role in U87-MG cell viability, adhesion, migration, invasion, clonogenic properties and the reorganization of the actin cytoskeleton. For instance, PIMT inhibition by siRNA reduced cell migration and invasion by different assays: in wound healing assay, in Boyden chambers coated with gelatin and in Matrigel invasion assay. Conversely, in stably transfected U87-MG cells overexpressing wild-type PIMT, cell migration, invasive capacity and colony formation significantly increased. However, in stably transfected cells with the gene encoding for the inactive PIMT D83V, in spite of its overexpression, the migration and invasion remained similar to that observed in control cells transfected with the empty plasmid. In all these conditions, cell viability was unaffected. Finally, the reorganization of the actin cytoskeleton is regulated by PIMT protein level. Overall, these data enlighten the importance of PIMT level and mainly of its catalytic activity in migration and invasion of malignant glioma U87-MG cells and its possible contribution in cancer cell invasion during glioblastoma growth.
Citation Format: Fatima Belkourchia, Richard Desrosiers. To analyse PIMT function in glioblastoma cell invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4603.
Abstract 4604: Kidney injury molecule-1 regulates metastasis in renal cell carcinoma
Authors: Lee Jasper C. , Sarabusky Marie A. , Champagne Audrey , Lucien Fabrice , Gunaratnam Lakshman 
Published: August 2019

Abstract
Over 30% of patients with renal cell carcinoma (RCC) present with metastases, with median survival of 2 years. Kidney injury molecule 1 (KIM-1) is a cell-surface glycoprotein expressed by &gt;85% of RCC tumours and may serve as an early biomarker for RCC detection. Here we sought to determine if tumour KIM-1 plays a role in RCC cell extravasation and metastasis to lungs. Methods: We overexpressed KIM-1 in Renca cells (murine RCC) using stable transfection of an expression plasmid, or silenced endogenous KIM-1 in human 769-P and 786-O RCC cells using shRNA. We studied extravasation using the chorioallantoic membrane (CAM) model. We injected ~1x105 Renca or 769-P cells into blood vessels of chicken embryos (n=6), and measured percentage of cells that exited the capillary bed into surrounding spaces after 24 hours. To study lung metastasis, we injected ~5x105 Renca or 786-O cells intravenously through the tail vein of syngeneic BALB/c (n=10/group) or immune deficient Rag1-/- [BALB/c] (n=5/group) mice, and manually counted metastatic nodules in excised lungs after 17 days. Finally, we analyzed the publicly available Cancer Genome Atlas Illumina RNA-Seq dataset to determine if KIM-1 mRNA expression predicts overall survival in patients with clear cell RCC. Results: In CAM experiments, extravasation efficiency was significantly decreased in KIM-1pos 769-P cells compared to KIM-1neg 769-P cells (30.08% vs. 47.94%; p=0.0004), and in KIM-1pos Renca cells compared to KIM-1neg Renca cells (47.78% vs 60.73%; p=0.042). BALB/c mice injected with Kim-1pos Renca cells or Kim-1pos 786-O cells had significantly fewer lung metastases compared to mice injected with Kim-1neg Renca cells or Kim-1neg 786-O cells, respectively (257 vs 429, p=0.02; 131 vs 339 p=0.001). The inhibitory effect of KIM-1 expression in Renca and 786-O cells on numbers of lung metastases was similar in Rag1-/- mice, suggesting that the observed effects were not dependent on adaptive immunity. In the TCGA database, patients with the lowest vs. highest tertile of KIM-1 RCC expression has significantly higher mortality (unadjusted HR 1.82, 95% CI 1.23-2.70; p=0.0034). Conclusion: KIM-1 is a negative regulator of cell extravasation and inhibits the development of lung metastases in mice, and KIM-1 expression in human RCC may predict better survival. Deciphering the underlying mechanisms may lead to novel therapies.
Citation Format: Jasper C. Lee, Marie A. Sarabusky, Audrey Champagne, Fabrice Lucien, Lakshman Gunaratnam. Kidney injury molecule-1 regulates metastasis in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4604.
Abstract 4613: Mathematical modeling of tumor growth in mouse models
Authors: Zhang Chao , Jiang Xiaoqian , Guo Sheng , Li Qixiang 
Published: August 2019

Abstract
A variety of tumor models are used in preclinical oncology drug discovery, including patient-derived xenografts (PDXs), cell line-derived xenografts (CDXs), and syngeneic homografts. Tumors in mouse models exhibit heterogeneous growth patterns with or without drug treatment, which is further complicated by measurement errors. Mathematical modeling of tumor growth helps us better understand such patterns and analyze drug efficacy in transplanted tumor models. Many mathematical models have been proposed to describe tumor growth curves, each with certain assumptions and equations, suitable for specific situations or data sets1-5. It is yet unknown which models are best in fitting the growth curves for a large collection of mouse models. In this study, we systematically evaluated a set of mathematical models including exponential models, logistic and Gompertz model, biphasic models, dynamic carrying capacity model, and power law model on more than 50,000 tumor growth datasets collected from in vivo efficacy studies in PDXs, CDXs and syngeneic models. A set of metrics were used to evaluate the goodness of fit, including Akaike Information Criterion (AIC), root mean square error (RMSE), coefficient of determination, mean absolute relative error, etc. We also proposed a new composite metric to combine many criteria for easy selection of growth models. Our results show that tumor growth patterns are less complex under vehicle treatment, and different mathematical models have relatively small difference in modeling the growth curves. Tumor growth patterns are more diverse under drug treatment. Tumors may shrink or completely remit, though some may grow in the first days after inoculation before drug effect takes place. Still some tumors stop growing or even shrink before drug resistance develops and resume fast growing. Therefore, different mathematical models are needed to describe the different patterns. Finally, we present summary statistics to give an overall picture on the applicability of the mathematical models, and suggest statistical models for subsequent analysis for drug efficacy evaluation and biomarker discovery.
Citation Format: Chao Zhang, Xiaoqian Jiang, Sheng Guo, Qixiang Li. Mathematical modeling of tumor growth in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4613.
Abstract 462: Results from multiple datasets including the TCGA reveal limited clinical significance of molecular subtypes in bladder cancer
Authors: Lahorewala Sarrah S. , Morera Daley S. , Wang Jiaojiao , Lokeshwar Vinata B. 
Published: August 2019

Abstract
INTRODUCTION AND OBJECTIVE: Molecular subtypes have been suggested to predict outcome in patients with muscle invasive bladder cancer (MIBC). The major subtypes reported have been “luminal” and “basal”; however, there is little consensus regarding subtype-signatures and the clinical parameters used to evaluate outcome. The objective of this study was to examine using multiple datasets, if molecular subtypes are distinct entities within MIBC and whether they predict clinical outcome.
METHODS: We analyzed transcriptome data from all 402 MIBC samples in The Cancer Genome Atlas (TCGA) and 151 high-grade MIBC samples from three datasets in Oncomine™. Transcript levels were also measured in 52 bladder tumor specimens with clinical follow-up (cohort-1). Samples were subtype-scored using gene panels (GP-11, GP-30, BASQ) consisting only of those genes common among published studies. Correlation of subtypes to recurrence/progression-free survival (R/PFS), metastasis, cancer-specific survival (CSS) and overall-survival (OS) was examined by logistic regression, Cox proportional Hazards model and Kaplan-Meier analyses.
RESULTS: Based on GP-11 subtype-scoring, &gt;75% of the MIBC TCGA-dataset samples were mixed, i.e. neither pure-luminal nor pure-basal. When tumors were categorized as pure-luminal, pure-basal, or mixed, the subtypes could not predict OS or R/PFS. Consistent with published studies, when tumors were categorized as luminal or basal the subtypes predicted OS (P=0.051); sensitivity: 53.9%; specificity: 62%. Subtypes also correlated with tumor-grade (P=0.0005); most low-grade MIBC cases (16/21) in the TCGA-dataset were luminal. However, MIBC is rarely low-grade and subtypes could not predict OS (P=0.131) when only high-grade cases were included. Subtypes were not significant prognosticators in multivariate analyses. GP-30 and BASQ panels validated these results. In the Oncomine-dataset and cohort-1, subtypes could not predict metastasis, CSS, or OS.
CONCULUSIONS: Our study of multiple datasets reveals that molecular subtypes may reflect tumor-heterogeneity but are likely not distinct entities within MIBC. Furthermore, molecular subtypes have limited prognostic capability for MIBC patients. Although there is a need to individualize patient care, further examination into the molecular subtypes of MIBC is needed before their incorporation into clinical practice.
Citation Format: Sarrah S. Lahorewala, Daley S. Morera, Jiaojiao Wang, Vinata B. Lokeshwar. Results from multiple datasets including the TCGA reveal limited clinical significance of molecular subtypes in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 462.