bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 51: Stromal AKT2 controls epithelial invasions
Authors: Cichon Ann-Christin , Pickard Adam , Patel Daksha , McCance Dennis 
Published: August 2012

Abstract
The tumor microenvironment is gaining importance in the regulation of tumorigenesis, invasion and metastasis. Loss of PTEN, a negative regulator of AKT, in stromal fibroblasts results in an increased tumor occurrence in ErbB2 expressing murine mammary tumors. Furthermore, we have shown that activation of AKT in stromal fibroblasts, following loss of the Retinoblastoma Protein (Rb), induces epithelial invasions in organotypic raft cultures, via an increase in Keratinocyte Growth Factor (KGF) expression. In addition, we have shown that loss of the PTEN tumor suppressor in stromal fibroblasts and subsequent activation of AKT, increases invasive potential of Human Papilloma Virus Type 16 E6 and E7 expressing keratinocytes. This is mediated by an increase in KGF expression. There are three isoforms of AKT expressed in human fibroblasts, AKT1, AKT2 and AKT3. By depleting each individual AKT isoform in stromal fibroblasts we have been able to establish that AKT2 is essential in regulating the cross talk between epithelium and stroma, and depletion of stromal AKT2 inhibits invasions. However, loss of stromal AKT2 does not function exclusively through regulation of KGF levels as it activates a second, protective pathway, which is able to counteract the effects of KGF. This protective pathway is mediated by increased Interleukin1 beta levels produced by the fibroblasts. Preliminary data from head and neck cancer specimens show that AKT is activated in stroma of cells associated with tumor but not normal tissue. Future work will determine the AKT dependent pathways that lead to increased KGF and Interleukin1 beta expression as well as how these factors mediate invasions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 51. doi:1538-7445.AM2012-51
Abstract 5102: Identifying targets for melanoma therapy: Biological and clinical implications of BRAF L597 mutants
Authors: Dahlman Kimberly Brown , Xia Junfeng , Hutchinson Katherine , Hucks Donald , Jia Peilin , Su Zengliu , Hicks Donna J. , Netterville James L. , Vnencak-Jones Cindy L. , Sosman Jeffrey , Zhao Zhongming , Pao William 
Published: August 2012

Abstract
Recurrent driver mutations in BRAF (V600), NRAS (G12/13, Q61), KIT (W557, V559, L576, K642, D816), GNAQ (Q209) and GNA11 (Q209) have previously been identified in malignant melanomas, but over one-third of cases have no known potentially actionable targets. To identify novel drivers, we performed whole-genome sequencing of a tumor-normal pair from a patient with an aggressive, chemotherapy-naïve metastatic melanoma which was pan-negative for the mutations listed above. Our data analysis pipeline revealed the landscape of somatic single nucleotide polymorphisms (SNPs), insertions and deletions, copy number variations, and structural variants. A subset of the nonsynonymous SNPs was validated by direct sequencing, resulting in the identification of a somatic BRAF L597R mutation. Surrogate kinase assays suggest that this mutant is sensitive to both BRAF and MEK inhibitors. Subsequent mutational analyses showed that BRAF L597 mutations were in 2 of 34 (6%) ‘pan-negative’ tumors. Collectively, these data demonstrate the frequency and potential therapeutic implications of BRAF L597 mutations in melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5102. doi:1538-7445.AM2012-5102
Abstract 5104: Identification of key tumorigenic pathways in pancreatic adenocarcinoma patients using massively parallel DNA and RNA sequencing
Authors: Liang Winnie S. , Craig David W. , Carpten John , Borad Mitesh J. , Demeure Michael J. , Weiss Glen J. , Kiefer Jeffrey A. , Posner Richard , Hostetter Galen H. , Izatt Tyler , Sinari Shripad , Christoforides Alexis , Aldrich Jessica , Kurdoglu Ahmet , Phillips Lori , Benson Hollie , Baker Angela , Han Haiyong , Lake Douglas , Stites Edward C. , Ramanathan Ramesh K. , Fonseca Rafael , Stewart A. Keith , Hoff Daniel Von 
Published: August 2012

Abstract
Purpose: Pancreatic adenocarcinoma is among the most lethal forms of all malignancies. While significant research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult. The majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to assess global somatic events across multiple pancreatic tumors by using next-generation sequencing technologies (NGS). Experimental Design: We performed whole genome sequencing (WGS) on paired tumor and normal samples from 3 pancreatic adenocarcinoma patients. Additionally, we performed whole transcriptome sequencing (WTS) on 2 of these patients’ tumors for which tumor RNA was available. Results: We generated on average 132 billion mappable bases across all patients using WGS, and identified 140 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. Data from WGS and WTS were integrated and analyzed to identify the most heavily affected pancreatic cancer pathways across all patients. The KRAS signaling pathway was identified as the most significant map. Unbiased global pathway analysis was also performed to identify processes that may be impacted. Consistent with the previous analysis, the most significant pathway from this analysis is also KRAS signaling. This integrated analysis specifically identifies heavily affected pathways in pancreatic cancer and pinpoints genes and processes that may be considered as targets for more effective therapies. Conclusions: While sequencing of additional patients is necessary to strengthen selection of key pathways, we demonstrate the utility of using NGS to understand the processes driving pancreatic adenocarcinoma so that standardized treatments for patients may be improved.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5104. doi:1538-7445.AM2012-5104
Abstract 5106: A HHIP derived gene expression signature for the prediction of patient survival after adjuvant chemotherapy of pancreatic cancer
Authors: Pilarsky Christian , Gorille Tobias , Rückert Felix , Grützmann Robert , Saeger Hans Detlev 
Published: August 2012

Abstract
Prognosis for patients with pancreatic carcinoma (PDAC) remains poor. Despite of increasing knowledge about the molecular basis of PDAC neither a specific marker for early diagnosis nor target proteins for a new therapeutic approach have been identified so far. However, reliable prediction of survival might help to improve the therapeutic outcome for patients with PDAC. In recent years it has become evident, that the Hedgehog (Hh) signal transduction pathway is a key regulator of pancreatic cancer development. Hedgehog interacting protein (HHIP) is a key modulator of Hh action and is overexpressed in the tumor stroma of PDACs. Reasoning that HHIP could serve as an indicator of Hh signaling activation we identified HHIP associated genes (HAG) using guilt by association (GBA) analysis in a set of PDAC gene expression profiles from microdissected tissue. Using the Affymetrix GeneChip U133 2.0 array and TNASAS we analyzed the gene expression profile of 59 PDAC samples and identified prognostic marker from HAG for survival of PDAC patients with adjuvant therapy. GBA analysis of gene expression profiles from microdissected PDAC tissue yielded 276 HAGs. TNASAS analysis using these genes revealed a prognostic gene expression signature of 50 genes, which was able to identify patients receiving adjuvant therapy with gemcitabine surviving more than 24 month with a total error of 0.087. TNASAS analysis of samples from patients treated without adjuvant therapy failed to identify a gene set with prognostic significance. Gene expression analysis is able to identify genes with prognostic significance in patients with adjuvant chemotherapy. These genes seem to be correlated with the efficacy of adjuvant gemcitabine therapy. Further analysis of those genes can reveal more insights in the signal transduction mechanisms associated with those genes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5106. doi:1538-7445.AM2012-5106
Abstract 5109: Identical cancer cell lines from Sanger & Broad CCLE programs sometimes differ
Authors: Doman Thompson N. 
Published: August 2012

Abstract
The Sanger Institute in the UK has an ongoing initiative termed the “Cancer Genome Project” to systematically characterize the genetics and genomics of 770 cancer cell lines. Similarly, the Broad Institute in the US collaborates on the “Cancer Cell Line Encyclopedia” or CCLE project, entailing the eventual characterization of approximately 1000 cancer cell lines. At present, there are over 400 cell lines shared by these two initiatives. As part of a number of computational efforts in cancer biology we have used data from these two programs and have observed some unexpected differences in cell lines at the DNA and/or transcript level as well as some phenotypic differences, and we present here an analysis of these results including implications to the use of cancer cell lines in drug discovery and the larger question of genomic stability in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5109. doi:1538-7445.AM2012-5109
Abstract 5111: Selection vs modification in cancer
Authors: Gorlov Ivan P. , Byun Jinyoung , Gorlova Olga , Logothetis Christopher , Zhao Hongya 
Published: August 2012

Abstract
Tumors differ from normal tissues by a distinct pattern of up- and down-regulated genes. A difference in gene expression profiles between normal and tumorous tissues can be (1) a result of the selection of preexisting variation in gene expression or (2) a modification of expression. In the simplest scenario, for genes fitting the selection model (SM genes), one can expect to find bimodal distribution of the expression values in normal tissue with only 1 peak in the tumor tissue. For genes fitting the modification model (MM genes), one can expect significant differences in mean gene expression values, with a similar expected variance in normal and tumorous tissues. Using these criteria and Gene Expression Omnibus (GEO) data, we have identified 200 SM genes and 200 MM genes. To identify SM and MM genes, we analyzed the distribution of gene expression values in normal prostate tissue derived from prostate free of any pathologic alterations (NP), normal-appearing prostate tissue adjacent to tumor (NA), primary prostate tumor (PT), and prostate tumor metastasis (MPT). We identified 3 sets of SM genes: (1) bimodal distribution in NP and unimodal in PT, (2) bimodal distribution in NA and unimodal in PT, and (3) bimodal distribution in PT and unimodal in MPT. Similarly, we identified 3 sets of MM genes. We found that SM genes are enriched by actin cytoskeleton genes for all 3 sets of genes: for set 1, P&lt;10E-13; for set 2, P&lt;10E-11; and for set 3, P&lt;10E-2. MM genes were enriched by the genes from cancer-related pathways (P&lt;10E-6) in set 1 and regulation of cell proliferation (P&lt;10E-1) in set 2; no specific enrichment was found in set 3. We have also estimated an overlap between candidate genes for prostate cancer identified in genome-wide association studies (GWAS) and SM genes. GWAS candidates were overrepresented among the first set selection genes (10 vs expected 0.003 ± 0.002) and in the second set of genes (4 vs expected 0.003 ± 0.003), but for the third set of the genes, there was no indication of the enrichment (0 vs expected 0.003±0.002). For the MM genes, there was no indication of GWAS candidate enrichment. Taken together, our results suggest that selection of the preexisting variation in gene expression is important for early stages of carcinogenesis, whereas modification of gene expression is more important for cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5111. doi:1538-7445.AM2012-5111
Abstract 5112: Foxa1 and Foxa2 are essential for gender dimorphism in liver cancer
Authors: Li Zhaoyu , Tuteja Geetu , Schug Jonathan , Kaestner Klaus H. 
Published: August 2012

Abstract
Hepatocellular carcinoma (HCC) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males, an effect that is dependent on sex hormones. The molecular mechanisms by which estrogens prevent and androgens promote liver cancer remain unclear. Here, we discover that sexually-dimorphic HCC is completely reversed in Foxa1- and Foxa2-deficient mice after diethylnitrosamine-induced hepatocarcinogenesis. Co-regulation of target genes by Foxa1/a2 and either the estrogen receptor (ERalpha) or the androgen receptor (AR) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/2-deficient mice. Thus, both estrogen-dependent resistance to and androgen-mediated facilitation of HCC depend on Foxa1/2. Strikingly, single nucleotide polymorphisms at FOXA2 binding sites reduce binding of both FOXA2 and ERalpha to their targets in human liver, and correlate with HCC development in women. Thus, Foxa factors and their targets are central for the sexual dimorphism of HCC. (Cell, accepted in press)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5112. doi:1538-7445.AM2012-5112
Abstract 5116: Identification and rapid in vivo validation of a novel drug combination for treating melanoma
Authors: Berndt Jason D. , Frazier Jason , Grenley Marc , Bahrami Bahram , Moon Randall T. , Olson Jim , Klinghoffer Richard 
Published: August 2012

Abstract
The well-established capability of tumors to resist single agent chemotherapies underscores the need to identify novel synergistic drug combinations to treat patients with cancer. Here we use an innovative arrayed needle technology to provide rapid in vivo validation of findings from a genome scale RNAi screen and reveal the potential of an unexpected drug combination to treat patients with melanoma. Our efforts focused on the β-catenin pathway. The β-catenin pathway impacts cancer progression in a context dependent manner. In some malignancies such as colon cancer, increased β-catenin activity drives oncogenesis. In contrast activation of β-catenin has been associated with decreased tumor proliferation and improved prognosis in patients with melanoma. A screen with an arrayed library of 14,000 lentiviral shRNA vectors revealed that silencing of dihydrofolate reductase, the target of the classic chemotherapeutic methotrexate, led to synergistic activation of the β-catenin pathway when combined with an inhibitor of GSK3. We therefore explored whether combination therapy, consisting of a GSK3 inhibitor and methotrexate could represent a potential treatment for melanoma patients. Two distinct small molecule inhibitors of GSK3, 6-bromoindirubin-3αoxime (BIO) and Chiron 99021, demonstrated synergy with methotrexate to activate β-catenin signaling in the melanoma cell line A375. To rapidly assess whether the observed synergy translates to the context of a living tumor, precision multiplexed microinjection using Presage technology was performed on mice harboring flank melanoma tumors. Discreet positions on each tumor were injected with either vehicle control, methotexate as a single agent, Chiron 99021 as a single agent, or the combination of the two agents. Analysis of the activation of beta-catenin and histology for markers of cellular proliferation, death, and differentiation allowed us to rapidly evaluate the efficacy of this drug combination. This rapid in vivo validation approach sets the stage for full preclinical evaluation of combined methotrexate and GSK3 inhibitor therapy using advanced co-clinical models of melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5116. doi:1538-7445.AM2012-5116
Abstract 5132: Pooled shRNA screens conducted in vitro and in vivo identify genes that are essential for the growth and/or survival of human tumor cells
Authors: Young Tara M. , Pasnikowski Elizabeth , Sahoo Padmini , Thurston Gavin , Daly Christopher 
Published: August 2012

Abstract
Identification of novel drug targets is a major challenge in cancer research. While numerous studies have identified genes that are mutated and/or amplified in cancers, the functional significance of most of these genetic alterations remains unknown. To directly identify genes that are required for the growth of human tumor cells, and that could potentially be targets for therapeutic monoclonal antibodies, we employed a custom shRNA library containing ∼13,000 shRNAs targeting 3,210 genes (∼4 shRNAs per gene) that encode cell surface or secreted proteins. Cultured tumor cells were infected with the virally-packaged shRNA library such that each shRNA (and an associated molecular barcode) was integrated into ∼200 cells. Cells that expressed shRNAs that target essential genes were progressively depleted from the population upon in vitro passage or following implantation into mice, resulting in decreased representation of those shRNAs/barcodes versus reference samples. In vitro screens were conducted in 3 colorectal cancer cell lines (HCT116, DLD1 and Colo320DM) and in NCI-H1975 lung cancer cells. About 1-3% of the genes in the library were identified as essential for tumor cell growth and/or survival in vitro. Importantly, these genes included positive controls such as PCNA that were included in the library to validate the screening procedure, as well as components of pathways that are known to control cell growth such as IGF-1R, Wnt9a, sonic hedgehog and RON. In vivo screens were performed with HCT116 and NCI-H1975 cells by implanting cells into mice immediately following shRNA integration. Representation of shRNAs versus the reference sample was assessed in small tumors (∼100 mm3) and in large tumors (1000 mm3). While we observed very few hits in small tumors, the number of hits in large tumors was greater than that observed in vitro (e.g., ∼3-fold higher for HCT116), suggesting that tumor growth in vivo is dependent on a larger set of genes than is cell growth in vitro. Interestingly, the genes that were uniquely essential in tumors versus in vitro included several that are involved in cell/cell adhesion (e.g., cadherin 24, claudin 3) and cell signaling (epidermal growth factor receptor). In summary, our shRNA screens focusing on secreted and cell surface targets have identified genes that may be essential for tumor growth, including many genes that have not previously been implicated in this process. Upon further validation, these genes could potentially serve as novel targets for therapeutic antibodies in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5132. doi:1538-7445.AM2012-5132
Abstract 5134: The identification and characterization of genetic variations in lung adenocarcinomas in a Japanese population
Authors: Mimaki Sachiyo , Suzuki Ayako , Matsushima Koutatsu , Suzuki Makito , Ogasawara Naomi , Suzuki Yutaka , Tsuchihara Katsuya , Esumi Hiroyasu 
Published: August 2012

Abstract
Lung adenocarcinoma is a major histological subtype of non-small cell lung cancer. Previous studies have revealed substantial clinical and molecular differences between the Asian and Caucasian populations. Kinase inhibitor-sensitive EGFR mutations are frequently detected in Asian, female and non-smoker population. These findings suggest unique genetic and/or environmental background of carcinogenesis of this tumor. In the present study, we generated and analyzed a dataset of single-nucleotide variants (SNVs) and small insertions and deletions (indels) in the entire exon regions (exomes) in Japanese lung adenocarcinomas. We chose consecutive 97 of surgically resected T2 cases registered to the database containing clinicopathological and lifestyle information established at National Cancer Center Hospital East. High integrity genomic DNA was extracted from archived methanol fixed paraffin embedded tissue samples. Whole exons were captured using Agilent SureSelect system and we generated 76-base paired-end sequences with an Illumina GAIIx platform. Approximately 30 million mapped sequences were obtained for each sample, providing 75x coverage of the target regions and 93% of the target regions also had 5x coverage. Using the sequence data, we identified SNVs and indels by BWA, SAMtools and GATK. EGFR mutations were observed among 55 cases and Sanger sequencing validated them. As well, known lung cancer-related gene mutations such as KRAS and TP53 were detected in exome data. Detailed profiling of somatic mutations provided wide variety of heterogeneity of known and novel gene mutations with both EGFR-mutant and -wildtype background. These heterogenity might define the unique signature of an individual tumor and be waited for further classification suitable for understanding genetic mechanism of carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5134. doi:1538-7445.AM2012-5134