bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5238: Acquired therapeutic resistance is mediated by deregulation of multiple pathways.
Authors: Heiser Laura M. , Shaw Chad A. , Wang Nicholas J. , Grasso Catie , Anur Pavana , Ng Sam , Goldstein Theodore , Spellman Paul T. , Stuart Joshua , Osborne Kent , Gray Joe , Schiff Rachel 
Published: August 2014

Abstract
The HER2-directed antibody, trastuzumab combined with chemotherapy, has markedly improved outcome of patients with HER2-amplified breast cancer, yet both de novo and acquired resistance occur in a substantial subset of patients. To study the molecular underpinnings of acquired resistance, we have developed a panel of 30 unique HER2+ cell lines that have been cultured to become resistant to lapatinib, trastuzumab and the combination treatment. Each of these models underwent next-generation sequencing to elucidate mechanisms of resistance to HER2 therapies. We hypothesized that resistance may be mediated by modulation of particular pathways - rather than by individual genes. With this idea in mind, we performed a PARADIGM pathway analysis that integrates information from multiple genomic data types to calculate pathway activity scores. The PARADIGM SuperPathways represent 1321 cell signaling pathways curated from sources such as KEGG, BioCarta, and Reactome. We populated the networks with the copy number (ExomeSeq) and expression (RNAseq) datasets that had been normalized to identify contrasts between parental and resistant lines. For each pathway, we computed a Pathway Activity Score as the sum of the absolute value of each node in the pathway, normalized by the total number of pathway nodes. Nearly 30% of the curated pathways (361/1321) are strongly deregulated in at least one of the network models, whereas a much smaller subset (3%) were strongly deregulated across multiple resistance cell line models. Frequently deregulated pathways include hemoglobin chaperone, ATM mediated phosphorylation of repair proteins, the HIF2alpha transcription factor network and the PLK signaling events in the cell cycle. All together, these findings indicate that resistance is mediated through many signaling mechanisms. Furthermore, the acquired resistance-related aberrations suggest possible second-line treatment strategies that may be effective.
Citation Format: Laura M. Heiser, Chad A. Shaw, Nicholas J. Wang, Catie Grasso, Pavana Anur, Sam Ng, Theodore Goldstein, Paul T. Spellman, Joshua Stuart, Kent Osborne, Joe Gray, Rachel Schiff. Acquired therapeutic resistance is mediated by deregulation of multiple pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5238. doi:10.1158/1538-7445.AM2013-5238
Abstract 5251: Role of mammalian Hippo Mst1/2 protein kinase signaling in lung cancer progression.
Authors: Cinar Bekir , Alptekin Almet , Natale Ronald B. 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) is a major lung adenocarcinoma observed in humans. Therapeutic options for patients with NSCLC are very limited and palliative since the disease mechanism is poorly understood. The Mst1/2 serine-threonine kinase, related to hippo (hpo) in drosophila, has emerged as an important regulator of tumorigenesis with poorer prognosis. However, the biological significance of Mst/Hippo in lung cancer pathogenesis remains to be determined. In this study, we assessed Mst1/2 expression at protein levels by western blots in cultures and in primary and metastatic lung cancer tissues by immunohistochemistry, and investigated the potential functional link between EGFR and Mst/Hippo signaling in well-characterized NSCLC cell models in vitro. We found that Mst1/2 protein levels were reduced by at least 50% in two out of five lung tumor cell lines analyzed. Surprisingly, reduction was observed in Erlotinib resistant H1734 and H1975 lung tumor cells. In agreement with this observation, Mst1 protein declined in primary lung tumor and was undetectable in metastatic lung cancer compared to non-cancerous counterparts. In addition, we showed that enforced Mst1 expression significantly increased sensitivity to EGFR inhibition by Erlotinib compared to mock treatment. We also showed that the activation of EGFR by epidermal growth factor (EGF) attenuated the Mst1 mediation of cell growth suppression. Taken together, our findings suggest that the loss of Mst/Hippo functions could contribute to lung tumor progression and acquired resistance to EGFR inhibitor. A molecular understanding of how these two opposing signals biochemically and functionally intersect may improve current EGFR blockade therapy.
Citation Format: Bekir Cinar, Almet Alptekin, Ronald B. Natale. Role of mammalian Hippo Mst1/2 protein kinase signaling in lung cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5251. doi:10.1158/1538-7445.AM2013-5251
Abstract 5253: SOX2-mediated cell survival and chemoresistance in lung cancer.
Authors: Chou Yu-Ting , Lee Chih-Chan , Hsiao Shih-Hsin , Lin Sey-En , Lin Sheng-Chieh , Wang Yuan-Hung , Wu Cheng-Wen 
Published: August 2014

Abstract
Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the stemness features remain elusive. Here we report the involvement of BCL2L1 in SOX2-mediated cell survival and chemoresistance in lung cancer. SOX2 was associated with poor prognosis in lung cancer patients and was expressed in a subclass of lung cancer cells the survival and chemoresistance of which were dependent on SOX2 stem cell signaling. SOX2 promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. Moreover, SOX2 knockdown attenuated tumor growth in a xenograft mouse model. SOX2 induced BCL2L1 expression, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 and BCL2L1 expression levels were significantly correlated in human lung tumors, supporting the involvement of BCL2L1 in SOX2-mediated oncogenesis. Our findings reveal for the first time that SOX2-BCL2L1 signaling maintains mitochondrial integrity and enhances cell survival, leading to increased chemoresistance in lung cancer cells.
Citation Format: Yu-Ting Chou, Chih-Chan Lee, Shih-Hsin Hsiao, Sey-En Lin, Sheng-Chieh Lin, Yuan-Hung Wang, Cheng-Wen Wu. SOX2-mediated cell survival and chemoresistance in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5253. doi:10.1158/1538-7445.AM2013-5253
Abstract 5266: Stat3 is a positive regulator of gap junctional intercellular communication in cultured, human lung carcinoma cells.
Authors: Geletu Mulu , Arulanandam Rozanne , Greer Samantha , Trotman-Grant Aaron , Tomai Evangelia , Raptis Leda 
Published: August 2014

Abstract
Neoplastic transformation of cultured cells by a number of oncogenes such as src suppresses gap junctional, intercellular communication (GJIC); however, the role of Src and its effector Signal transducer and activator of transcription-3 (Stat3) upon GJIC in non small cell lung cancer (NSCLC) has not been defined. Immunohistochemical analysis revealed high Src activity in NSCLC biopsy samples compared to normal tissues. Here we explored the potential effect of Src and Stat3 upon GJIC, by assessing the levels of tyr418-phosphorylated Src and tyr705-phosphorylated Stat3, respectively, in a panel of NSCLC cell lines. Gap junctional communication was examined by electroporating the fluorescent dye Lucifer yellow into cells grown on a transparent electrode, followed by observation of the migration of the dye to the adjacent, non-electroporated cells under fluorescence illumination.
The results demonstrated an inverse relationship between Src activity levels and GJIC; in five lines with high Src activity GJIC was absent, while two lines with extensive GJIC (QU-DB and SK-LuCi6) had low Src levels, similar to a non-transformed, immortalised lung epithelial cell line. Interestingly, examination of the mechanism indicated that Stat3 inhibition in any of the NSCLC lines expressing high endogenous Src activity levels, or in cells where Src was exogenously transduced, did not restore GJIC. On the contrary, Stat3 downregulation in immortalised lung epithelial cells or in the NSCLC lines displaying extensive GJIC actually suppressed junctional permeability. Moreover, expression of the constitutively active form of Stat3, Stat3C caused an increase in gap junctional communication.
Our findings demonstrate that although Stat3 is generally growth promoting and in an activated form it can act as an oncogene, it is actually required for gap junctional communication both in nontransformed lung epithelial cells and in certain lung cancer lines that retain extensive GJIC.
Citation Format: Mulu Geletu, Rozanne Arulanandam, Samantha Greer, Aaron Trotman-Grant, Evangelia Tomai, Leda Raptis. Stat3 is a positive regulator of gap junctional intercellular communication in cultured, human lung carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5266. doi:10.1158/1538-7445.AM2013-5266
Abstract 5269: Divergent roles of Akt isoforms in insulin-like growth factor-mediated lung tumorigenesis.
Authors: Franks Sarah Elizabeth , Moorehead Roger A. 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer related mortalities worldwide. Akt is an important kinase in the PI3K pathway of growth factor signaling, and increased Akt activation in lung cancer is associated with poor prognosis. Akt regulates cell growth, proliferation, survival, metabolism and migration making it an attractive target for molecular therapies. Akt exists as three isoforms (Akt1-3) and while it was previously thought they were largely redundant in activity, evidence of differing roles is emerging. Our lab has generated a doxycycline-inducible, tissue-specific transgenic mouse model of lung cancer. Using a surfactant protein C (SPC) promoter, the type I insulin-like growth factor receptor (IGF-IR) is overexpressed in type II alveolar cells which initiates the development of tumors in the lungs. Following nine months of treatment with doxycycline, macroscopic tumors are present on 100% of transgenic mice. These lung adenomas typically present as one or more discrete nodules on the surface of the lung. In this model, cells expressing high levels of IGF-IR also had higher levels of activated Akt. To investigate the role of specific Akt isoforms in lung tumorigenesis, these SPC-IGFIR transgenic mice were crossed with Akt1 null or Akt2 null mice to generate SPC-IGFIR-Akt1-/- and SPC-IGFIR-Akt2-/- mice. The Akt1 null SPC-IGFIR mice have reduced tumor burden compared to their Akt wild-type counterparts. In contrast, the absence of Akt2 accelerates tumor growth in SPC-IGFIR mice. Tumors formed in Akt1 null mice maintain the phenotype of distinct nodules. However, in the advanced tumor progression seen in Akt2 null mice the tumor tissue appears to permeate the lungs rather than form large nodules. These tumors are currently being characterized through evaluation of intracellular signaling as well as rates of proliferation and apoptosis. Initial results indicate opposing roles of Akt1 and Akt2 in the development and progression of lung cancer. While pan-Akt inhibitors are currently in clinical trials, our data suggests targeting Akt1 may be a more effective therapeutic strategy for lung cancer. However, further understanding of the function of each Akt isoform in lung cancer is needed.
Citation Format: Sarah Elizabeth Franks, Roger A. Moorehead. Divergent roles of Akt isoforms in insulin-like growth factor-mediated lung tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5269. doi:10.1158/1538-7445.AM2013-5269
Abstract 5270: The role of EphA2 in the maintenance of cell viability of KRAS mutant non-small cell lung cancer.
Authors: Amato Katherine R. , Chen Jin 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer-related deaths in the United States. Non-small cell lung cancer (NSCLC) is the most common histological subtype of lung cancer, which can be further subdivided based on its unique profile of oncogenic mutations. Identifying molecular subtypes of NSCLC and matching patients with appropriate targeted therapies is critically important for the treatment of this disease. Although significant progress has been made to develop novel, molecularly-targeted therapeutics, challenges still remain in targeting commonly occurring mutations in NSCLC, such as those in KRAS. Overcoming these challenges will require astute strategies to identify and inhibit novel kinase targets required for cell viability in these subtypes of lung cancer. To this end, we have shown that the EphA2 receptor tyrosine kinase plays a unique role in the maintenance of cell viability in NSCLC, especially those with KRAS mutations. EphA2 is generally overexpressed in NSCLC and even further overexpressed in KRAS mutant NSCLC. Preliminary data from our lab has shown that knockdown of EphA2 expression in a large number of human NSCLC cell lines dramatically inhibits cell viability in cell lines bearing KRAS mutations. To further understand this phenotype, we are working to define the molecular mechanisms downstream of EphA2 that are critical for cell viability in this genotype and to model the effects EphA2 deficiency in vivo using transgenic mouse models. Based on our preliminary data, we propose that EphA2 provides a novel target for modulating cell viability in lung cancers with KRAS mutations associated with limited therapeutic options.
Citation Format: Katherine R. Amato, Jin Chen. The role of EphA2 in the maintenance of cell viability of KRAS mutant non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5270. doi:10.1158/1538-7445.AM2013-5270
Abstract 5281: Insulin-mediated regulation of the miR132/212 cluster and miR 122/181a expression through PI3K, Akt, mTOR signaling in primary cultured rat hepatocytes.
Authors: Shukla Upasana , Tumma Nithin , Gratsch Theresa , Dombkowski Alan , Novak Raymond 
Published: August 2014

Abstract
Background and Objective: Several microRNAs were selected for characterization of their response to insulin signaling based on previous reports implicating their role in the regulation of hepatic metabolism, diabetes, hepatocellular carcinoma, and predictions of targeting CYP2E1. CYP2E1 catalyzes the metabolic activation of carcinogens, increases cellular oxidative stress, and is elevated in diabetes and at low insulin levels (0.1nM) in primary cultured hepatocytes. In addition, aberrant miR-122 expression was reported to be associated with hepatocellular carcinoma in rats, as well as in human tissue, and may be involved with hepatocarcinogenesis. In view of the critical role of the PI3K, Akt and mTOR signaling pathway in pathogenesis, mechanistic studies were conducted to examine the role of this pathway in regulation miR 132/212, 122 and 181a expression. Methods: Insulin effects on miRNA (miRs) levels were monitored using qPCR, and mechanistic studies employing inhibitors of PI3K, Akt, and mTOR were used to examine the role of this insulin signaling pathway on miR expression. The results were compared to miR let-7a, which is not implicated in the regulation of hepatic metabolism or diabetes and does not target CYP2E1 mRNA. Results: Insulin at concentrations of 0.1, 1.0, and 10 nM increased the expression of miRNA-132 and 212 ∼2- and 1.8-fold respectively, whereas expression of miRNAs 181a and 122 increased ∼1.6- and 1.4-fold, respectively. In contrast, insulin failed to significantly alter the expression of miRNA let-7a. Inhibition of PI3K with LY294002, Akt with A-443654 and mTOR with rapamycin resulted in significant suppression of the insulin-mediated elevation of miR-132, miR-212, and miR-122 levels monitored over the insulin concentrations examined. Inhibition of PI3K with LY294002, or Akt with A-443654 decreased the insulin-mediated increase in miR-181a levels by ∼20 to 50% relative to the respective insulin-concentration. Rapamycin inhibition of mTOR produced a marginal (&lt;10%) decrease in miR-181a levels. Inhibition of PI3K or Akt did not show any significant effect on miR let-7a. In summary, seminal evidence is provided for insulin regulation of microRNA expression in primary cultured hepatocytes through PI3K, Akt and mTOR (TORC1).
Citation Format: Upasana Shukla, Nithin Tumma, Theresa Gratsch, Alan Dombkowski, Raymond Novak. Insulin-mediated regulation of the miR132/212 cluster and miR 122/181a expression through PI3K, Akt, mTOR signaling in primary cultured rat hepatocytes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5281. doi:10.1158/1538-7445.AM2013-5281
Abstract 5284: A microRNA downregulated in human cholangiocarcinoma induces G2/M arrest through multiple targets.
Authors: Yamanaka Sumitaka , Campbell Nathaniel R. , Kuo Scot C. , Mezey Esteban , Maitra Anirban , Selaru Florin 
Published: August 2014

Abstract
Background: Cholangiocarcinomas (CCA) are cancers with dismal prognosis, thought to arise from epithelial cells lining the biliary tree. An improved understanding of the pathogenesis of CCA, as well as novel diagnostic and therapeutic approaches are direly needed. MicroRNAs (miRs) are short, single-stranded sequences of RNA, that were recently demonstrated to play a major role in the regulation of virtually all cellular processes. Several previous studies identified miRs that are dysregulated in CCA as well as distinct roles played by miRs in CCA genesis or progression. Methods: We performed microRNA-arrays on 5 normal biliary duct epithelias and 5 CCAs that had been obtained at surgery. After data analysis, we selected mir-494 for all subsequent analysis among top 5 miRs. To confirm the initial miR array data, quantitative real time RT-PCR analysis was performed using 12 human CCA as well as 5 normal cholangiocyte specimens. And then, we transfected 2 CCA cell lines with miR-494 and a non-specific mimic, respectively, and performed mRNA arrays to identify in an unbiased fashion the genes whose expression is downregulated by miR-494. Furthermore, we performed fluorescence activated cell sorting, as well as differential interference contrast microscopy.
Results: miR-494 is significantly downregulated in human CCA specimens. Cells transfected with miR-494 showed a significant decrease in growth in the cell proliferation assay. As for the results of mRNA array, Ingenuity Pathway Analysis also indicated that miR-494 appears to coordinately affect several genes involved in the Mitotic Roles of Polo-like Kinase and Cell cycle: G2/M Checkpoint Regulation canonical pathways. We verified that miR-494 modulates the protein level of six genes involved in the G2/M transition. Next, we identified direct binding of miR-494 to the open reading frame (ORF), and downregulation of PTTG1 and TOP2A. Conclusions: our findings suggest that miR-494 has a global regulatory role in cell cycle progression. Therefore, it appears that the simultaneous effects of a single miR species on multiple targets along the same canonical pathway is advantageous for the usage of miRs as therapeutics.
Citation Format: Sumitaka Yamanaka, Nathaniel R. Campbell, Scot C. Kuo, Esteban Mezey, Anirban Maitra, Florin Selaru. A microRNA downregulated in human cholangiocarcinoma induces G2/M arrest through multiple targets. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5284. doi:10.1158/1538-7445.AM2013-5284
Abstract 5288: Identification of critical microRNA regulated pathways in histiocytic diseases.
Authors: Gregory-Bryson Emmalena , Parys Maciej , Kiupel Matti , Yuzbasiyan-Gurkan Vilma 
Published: August 2014

Abstract
Histiocytic diseases encompass a spectrum of proliferative diseases in humans and dogs. While relatively rare in the human, histiocytic diseases are quite prevalent in certain breeds of dog. In the dog, these diseases range from benign histiocytoma to the malignancy, histiocytic sarcoma (HS). Disseminated HS has a poor prognosis and lacks effective treatment options. The goal of this study is to unravel the mechanisms of tumorigenesis in histiocytic diseases by analyzing the differential expression of microRNAs (miRNAs) along the spectrum of canine histiocytic diseases. As regulators of gene expression, miRNAs will provide insight into the pathways for tumorigenesis in histiocytic malignancies as compared to benign histiocytic diseases. MiRNA profiling of canine histiocytic diseases was conducted on cases of reactive histiocytosis, histiocytic sarcoma, and hemophagocytic histiocytic sarcoma. These samples were compared to normal canine histiocytes derived from peripheral blood. Based upon analysis of the profiling data, several miRNAs were selected for verification and quantification by quantitative reverse transcription PCR. The expression of the known canine miRNAs was evaluated by miRNA array. Data analysis with unsupervised clustering resulted in miRNA expression pattern clusters that were similar to the disease groups. The miRNA profiling data revealed three miRNA targets that were significantly upregulated in all cases as compared to normal canine histiocytes. Functional studies of these miRNAs are underway. These findings support the hypothesis that each histiocytic disease entity has a unique miRNA profile. These miRNAs and/or genes in the pathways they regulate may be targeted for novel and effective therapies. Comparative studies have the potential to elucidate HS tumorigenesis, and improve clinical outcome in dogs and humans.
Citation Format: Emmalena Gregory-Bryson, Maciej Parys, Matti Kiupel, Vilma Yuzbasiyan-Gurkan. Identification of critical microRNA regulated pathways in histiocytic diseases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5288. doi:10.1158/1538-7445.AM2013-5288