bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 397: Systematic functional annotation of somatic mutations in cancer
Authors: Liang Han , Ng Patrick Kwok-Shing , Li Jun , Jeong Kang Jin , Lu Yiling , Yi Song , Sahni Nidhi , Mills Gordon 
Published: August 2018

Abstract
Recent sequencing studies have identified thousands of unique somatic mutations across patient tumors. However, the functional impact of the vast majority of these mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant open reading frame generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of downstream signaling effects for select aberrations. We apply the platform to annotate &gt;1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. We show that our platform has higher sensitivity for characterizing weak drivers than pooled screening. Our data are accessible through the user-friendly, open-access data portal we created. Our study will facilitate the discovery of novel biomarkers, improvement of existing prediction algorithms, and development of new therapeutic approaches.
Citation Format: Han Liang, Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Yiling Lu, Song Yi, Nidhi Sahni, Gordon Mills. Systematic functional annotation of somatic mutations in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 397.
Abstract 398: Functional coding and noncoding drivers of EMT-mediated acquired drug resistance
Authors: Bainer Russell O. , Wilson Catherine , Callow Marinella , Feng Siyu , Costa Michael , Watanabe Colin , Mayba Oleg , Lin Eva , Martin Scott , Yauch Bob , Bourgon Richard , Klijn Christiaan 
Published: August 2018

Abstract
In response to diverse stimuli, tumor cells can undergo a process resembling the epithelial-mesenchymal transition (EMT) observed during development. During this transition, epithelial-like tumor cells acquire mesenchymal-like physiologic features, become more motile and invasive, and acquire insensitivity to many therapeutic agents. While the importance of this phenomenon to cancer treatment and patient outcomes is well known, considerable heterogeneity exists across experimental models of EMT, and diverse mechanisms have been proposed to explain its various associated malignant phenotypes. Consequently, the extent to which these processes are shared uniformly across instances of EMT, as well as their relative importance in treatment contexts, remains unclear. We have used RNAseq, ATACseq, and parallelized high-throughput cell viability screening to identify differences in gene expression levels, chromatin accessibility, and drug sensitivity that correlate with EMT in a series of cell line models. By contrasting these changes across different genetic backgrounds and mechanisms of EMT induction, we are able to identify sets of elements in the transcribed and noncoding genome that are characteristic of different modes of EMT induction. Then, by comparing these candidate sets with observed differences in acquired drug sensitivity in the respective models, we were able to define a set of genetic elements whose biologic activity is likely to influence the efficacy of these compounds. Finally, we used a series of targeted CRISPR-based knockout screens to assess the relative importance of these elements to the viability of isogenic epithelial-like and mesenchymal-like cells, alone and in the presence of multiple therapeutic drugs. Using this approach, we were able to validate known mechanisms of acquired drug resistance and identify new candidate effectors. Notably, we identify multiple candidate noncoding elements containing CTCF binding sites that appear to meaningfully influence cell viability in a drug-specific manner, potentially implicating genome conformational changes in acquired therapeutic resistance.
Citation Format: Russell O. Bainer, Catherine Wilson, Marinella Callow, Siyu Feng, Michael Costa, Colin Watanabe, Oleg Mayba, Eva Lin, Scott Martin, Bob Yauch, Richard Bourgon, Christiaan Klijn. Functional coding and noncoding drivers of EMT-mediated acquired drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 398.
Abstract 4001: Gremlin-1 augments the estrogen-related receptor α signaling: Implications for progression of breast cancer in synergistic manner
Authors: Park Sin-Aye , Choi Bae-Jung , Kim Wonki , Surh Young-Joon 
Published: August 2018

Abstract
Gremlin-1 (GREM1), one of the bone morphogenic protein (BMP) antagonists, is known to be involved in organogenesis, tissue differentiation, and pathogenesis of several renal disorders including fibrosis, inflammation, and diabetes. Recently, it has also been reported that aberrant epithelial GREM1 expression initiates colonic tumorigenesis. However, the role of GREM1 in breast cancer remain largely elusive. We observed that GREM1 expression was highly increased in human breast cancer cells and tissues obtained from breast cancer patients. Furthermore, its overexpression is associated with poor prognosis of breast cancer patients, especially those with estrogen receptor (ER)-negative tumors. Suppression of GREM1 expression significantly inhibited the proliferation of SKBR3 human breast cancer cells in culture and xenograft mammary tumor growth while its overexpression enhanced their viability and invasiveness. Estrogen-related receptor α (ERRα) is an orphan nuclear hormone receptor and has recently attracted attention as a novel therapeutic target in the management of triple-negative breast cancers. We observed that ERRα binds directly to GREM1 promoter and modulates GREM1 expression. The mRNA level of GREM1 was reduced by an inverse agonist of ERRα, XCT790 and also by siRNA silencing of ERRα. Conversely, the overexpression of ERRα with its co-factor peroxisome proliferator-activated receptor gamma co-activator 1-α increased the mRNA level of GREM1. Surprisingly, the transcriptional activity of ERRα was found to be regulated by GREM1. The promoter activity of ERRα and the mRNA levels of ERRα target genes were highly increased in GREM1-overexpressing breast cancer cells. Treatment of MCF-7 cells with recombinant GREM1 protein also enhanced the ERRα promoter activity and transcription of its target genes. Taken together, our study identifies for the first time that the GREM1 can act as a downstream signaling molecule of the transcription factor ERRα and suggests a positive feedback loop between ERRα and GREM1, highlighting GREM1 as a potential diagnostic and therapeutic target for the treatment of ER-negative breast cancer.
Citation Format: Sin-Aye Park, Bae-Jung Choi, Wonki Kim, Young-Joon Surh. Gremlin-1 augments the estrogen-related receptor α signaling: Implications for progression of breast cancer in synergistic manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4001.
Abstract 4018: Mutations of HER2 at L755 residue results in HER2 nuclear accumulation and enhances breast cancer stem cell activity
Authors: Wang Wen-Ling , Nie Lei , Huynh Kieu-Thanh , Chen Jhen-Yu , Yao Jing-Han , Hung Mien-Chie , Huang Wei-Chien 
Published: August 2018

Abstract
Background: HER2 plays a critical role in tumor progression and cancer stemness in breast cancer cells. Somatic mutations in HER2 gene have been observed in low HER2-expressing cancer cells and are correlated with insensitization to tyrosine kinase inhibitors. One of the most frequently altered residue is L755, which is located at kinase domain and near a putative nuclear export signal sequence, increasing kinase activity and is associated with lapatinib resistance. Moreover, the correlation between HER2 nuclear localization and drug-resistance and poor clinical outcome has been demonstrated in cancer patients. However, the roles of HER2 mutations in its nuclear distribution and its ability to enhance cancer stemness remain unknown.
Methods: We hypothesized that activation of HER2 mutations on amino acid L755 might affect HER2 cellular localization. To investigate the cellular localization of HER2 and the role of L755 mutations in expansion of cancer stem cells, T47D cell line clones expressing wile-type (WT) and mutant HER2 (L755P and L755S) were established. The cellular fractionation, immunofluorescence staining, and western blot analysis were employed to verify the cellular distribution of HER2 L755 mutations. Biochemical strategies were further performed to examine the interaction of HER2 L755 mutant and cellular transporters nuclear importers or exporters.
Results: Our results showed that ectopically expressed HER2 L755P and L755S mutants exhibited a higher nuclear retention via interrupting nuclear exporting complex formation. HER2 L755P and HER2 L755S showed higher abilities to associate with CRM1 and RanBP3 but reduced the binding capacity with Ran. The increases in tyrosine phosphorylation of CRM1 and RanBP3 were found by HER2 mutants and cause the defect in the formation of nuclear exporting complex. Additionally, the HER2 L755P and HER2 L755S-expressing cell lines showed higher levels of cancer stem cell markers, CD44 and ALDH1 and increased mammosphere formation.
Conclusion: HER2 L755P and L755S mutations enhance the HER2 nuclear localization and breast cancer stemness. This study provided new insight into the role of HER2 mutation in cancer stemness, and was helpful to develop novel prognostic markers for the therapeutic efficacy in breast cancer patients.
Citation Format: Wen-Ling Wang, Lei Nie, Kieu-Thanh Huynh, Jhen-Yu Chen, Jing-Han Yao, Mien-Chie Hung, Wei-Chien Huang. Mutations of HER2 at L755 residue results in HER2 nuclear accumulation and enhances breast cancer stem cell activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4018.
Abstract 403: Analysis of the functional consequences of single nucleotide polymorphisms in CYP3A4 gene to prostate cancer in men of African ancestry
Authors: Rotimi Solomon O. , Ogo Chidiebere Ndukwe , Ogunlana Olubanke Olujoke , Chinedu Shalom Nwodo , Akinremi Titi , Fatiregun Omolara , Buraimoh Funlayo , Alabi Adewunmi , Tijani Kehinde , Salako Ayo , Omonisi Emmanuel , Agaba Ruth , Odedina Folakemi 
Published: August 2018

Abstract
Prostate cancer (CaP) is the leading cause of cancer death among Black men and its pathogenesis is linked to testosterone metabolism. CYP3A4 deactivates testosterone and the polymorphisms of its gene are known to alter testosterone metabolism. In this study, computational techniques were used to investigate the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) in the CYP3A4 gene in African Americans exome sequence. A case-control study was also carried out on 100 prostate cancer patients and 100 controls, among Yoruba men in Nigeria, to investigate the allelic variants of CYP3A4*1B (rs2740574 A&gt;G) using polymerase chain reaction restriction fragment length polymorphism. A total of 22 nsSNPs were found in CYP3A4 gene of African American; out of which, 13 mutations (Q472R, M445T, K421R, R403C, I396T, L373F, R372I, I335T, T309I, V191A, D174H, R162W and S134C) were predicted to have deleterious effects on the CYP3A4 protein. The protein structural analysis of these amino acid variants revealed that M445T mutation could result in an increased free energy with a significant (p&lt;0.05) loss of allosteric site at M445, altered metal binding, and loss of catalytic site at R446. T309I mutation which also resulted in increase free energy was found to be associated with a loss of catalytic site at E308. All the Nigerian samples were homozygous for the variant CYP3A4*1B allele. Hence, the presence of GG homologous variant in the Yoruba population of Nigeria, coupled with the computationally predicted deleterious mutations, could contribute to the high prevalence and aggression of CaP in black men. These genetic variants identified through in silico analysis can provide a better understanding of the wide range of disease susceptibility associated with this gene in Black men and aid the development of new molecular diagnostic markers for CaP particularly in men of West African ancestry.
Citation Format: Solomon O. Rotimi, Chidiebere Ndukwe Ogo, Olubanke Olujoke Ogunlana, Shalom Nwodo Chinedu, Titi Akinremi, Omolara Fatiregun, Funlayo Buraimoh, Adewunmi Alabi, Kehinde Tijani, Ayo Salako, Emmanuel Omonisi, Ruth Agaba, Folakemi Odedina. Analysis of the functional consequences of single nucleotide polymorphisms in CYP3A4 gene to prostate cancer in men of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 403.
Abstract 4032: Pharmacogenomic analysis of acquired resistance can reveal effective drug combination in glioblastoma
Authors: Li Xiaolong , Martinez-Ledesma Juan , Zhang Chen , Gao Feng , Yung W.K. Alfred , Koul Dimpy 
Published: August 2018

Abstract
Targeted cancer therapies have produced substantial clinical responses, but glioblastoma multiforme (GBM) has poor response due to developing resistance. The goal is thus to design strategies to overcome resistance to targeted drugs. To address this, we have embarked on a new type of screening for resistant targets, by developing acquired resistant glioma models and using pharmacogenomic platform to identify the resistant targets. We have established several patient-derived in vivo glioma stem cells (GSC) models using a PI3K specific inhibitor BKM-120 by a selective pressure after a chronic drug treatment. The resistant cells were subjected to RNA-seq analysis as well as pharmacologic analysis utilizing high-throughput kinase drug library screening. Analysis of integrated RNA-seq and kinase drug library screening of resistant cells identified multiple effective drug combination. Activation of Aurora kinase A (Aurora A)/Polo-like kinase 1 (Plk1)/cyclin-dependent kinase (CDK) signaling pathway was predominant in resistant GSCs. Concomitant targeting of PI3K together with Aurora A, Plk1 or CDK1 had a synergistic growth inhibitory effect. In addition, the combined inhibition of Plk1 and PI3K resulted in tumor growth suppression and significant delay of acquired resistance in vivo. These observations suggest that cell cycle pathway serves as a major survival signal upon PI3K inhibition and provides a rationale for the combined use of PI3K and cell cycle inhibition to prevent acquired resistance in human GBM.
Citation Format: Xiaolong Li, Juan Martinez-Ledesma, Chen Zhang, Feng Gao, W.K. Alfred Yung, Dimpy Koul. Pharmacogenomic analysis of acquired resistance can reveal effective drug combination in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4032.
Abstract 4038: A functional genomics approach to the identification of genes involved in resistance to Oxaliplatin in colorectal cancer
Authors: Invrea Federica , Cavicchioli Francesca , Petti Consalvo , Russo Rosalia , Isella Claudio , Medico Enzo 
Published: August 2018

Abstract
Currently, the first line therapy for metastatic colorectal cancer (CRC) is the FOLFOX regimen, which includes Oxaliplatin in combination with Fluorouracil and Leucovorin. Responses to FOLFOX range from overt regressions (35%) to full resistance (25%), and eventually all patients become resistant. Indeed, the molecular mechanisms of Oxaliplatin resistance remain mostly to be understood. To identify genes involved in sensitivity/resistance to Oxaliplatin, we designed an integrated approach including forward genetic screens and computational analyses. The pipeline includes: (i) stable transduction of CRC cells with pooled shRNA libraries; (ii) Oxaliplatin treatment for six weeks to select a drug-resistant subpopulation; (iii) identification of shRNA constructs enriched in the Oxaliplatin-resistant subpopulation by next-generation sequencing analysis. We focused the shRNA libraries targeting phosphatases and ubiquitin conjugation pathway genes. The first are involved in several biological processes, reversing the biochemical activity of kinases and typically acting as feedback loop regulators. The second direct proteins to degradation by the proteasome regulating homeostasis, cell cycle, and DNA repair pathways. HCT116 CRC cells, markedly sensitive to Oxaliplatin, were transduced in duplicate with both shRNA libraries. After Oxaliplatin treatment for six weeks, resistant populations emerged from the library-transduced cells, but not from control-transduced cells. To reveal shRNA constructs responsible of such phenotype, we extracted genomic DNA from transduced cells and, upon amplification of shRNA constructs by targeted PCR and next-generation sequencing, we compared the repertoire of shRNA sequences in HCT116 cells selected with Oxaliplatin with that of cells grown in standard medium. Screening hits were then prioritized for functional characterization, resulting in a phosphatase (CDC25C) and an ubiquitin ligase candidate (DCAF17). In conclusion, we successfully setup a functional genomic screening for acquired resistance to Oxaliplatin in CRC. Specific shRNA constructs from both the phosphatase and ubiquitin ligase libraries were enriched after Oxaliplatin treatment, highlighting candidate genes whose loss of function could potentially drive resistances to Oxaliplatin.
Citation Format: Federica Invrea, Francesca Cavicchioli, Consalvo Petti, Rosalia Russo, Claudio Isella, Enzo Medico. A functional genomics approach to the identification of genes involved in resistance to Oxaliplatin in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4038.
Abstract 4083: Intrahepatic cholangiocarcinoma and gallbladder carcinoma mouse model based on transplantation of syngeneic tumor-initiating cells
Authors: Kasuga Akiyoshi , Semba Takashi , Takaishi Hiromasa , Kanai Takanori , Saya Hideyuki , Arima Yoshimi 
Published: August 2018

Abstract
Biliary tract cancers (BTCs) are relatively rare in the Western world, but the rates of BTCs have risen worldwide in the past few decades. BTCs, which arise from epithelial cells in bile ducts, include intrahepatic and extrahepatic cholangiocarcinomas, gallbladder carcinomas, and ampullary carcinomas. The differences between these subtypes are not fully understood because of the limited number of genetically engineered mouse models for BTCs. Genetic mutations in the KRAS gene and the epigenetic changes in Ink4a/Arf genes have been frequently detected in BTCs, and it has been considered that those alterations are associated with the development and maintenance of human BTCs. To clarify the biological features of intrahepatic cholangiocarcinomas and gallbladder carcinomas, we developed syngeneic mouse models based on a combination of organoid 3D cultures and the transplantation of oncogene-expressed syngeneic bile duct epithelial cells. We isolated the epithelial cell adhesion molecule (EpCAM)-positive intrahepatic bile duct epithelial cells and the gallbladder epithelial cells from the Ink4a/Arf knockout C57BL/6 mice, and the cells were maintained as organoids under 3D culture conditions. Those cells were then infected with retroviruses expressing KRASG12V. Lethal metastatic adenocarcinomas having differentiated components formed in our mice when we transplanted the KRASG12V-expressing cells into the livers of wild-type C57BL/6 mice. The tumors resembled human desmoplastic intrahepatic cholangiocarcinomas and gallbladder carcinomas. Our mouse models can be useful for investigating pathogenesis and therapeutic strategies for human BTCs.
Citation Format: Akiyoshi Kasuga, Takashi Semba, Hiromasa Takaishi, Takanori Kanai, Hideyuki Saya, Yoshimi Arima. Intrahepatic cholangiocarcinoma and gallbladder carcinoma mouse model based on transplantation of syngeneic tumor-initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4083.
Abstract 4087: Investigating the novel role of Hippo signaling in mouse pancreas
Authors: Gao Ming , Liu Jun , Sharkey Francis E. , Crawford Howard C. , Johnson Randy L. , Chen Yidong , Wang Pei 
Published: August 2018

Abstract
Background: Large tumor suppressor kinase 1 and 2 are the core kinases of the Hippo signaling pathway, and play critical roles in regulating cell growth and organ size during animal development. Inactivation of the Hippo signaling pathway has been demonstrated to initiate tumor development in certain organs. However, the function of Lats1&2 in the pancreas is still elusive. Methods and results: To investigate the function of Lats1&2 in the pancreas, we generated mice with adult pancreatic acinar cell-specific deletion of Lats1&2 genes. Interestingly, instead of enlarging of the pancreas or pancreatic tumorigenesis, the deletion of Lats1&2 genes in pancreatic acinar cells resulted in severe inflammation of the pancreas. To further examine the mechanisms, we took advantage of a Rosa26 reporter to trace individual Lats1&2 null cells in vivo. We found that the loss of Lats1&2 did not affect cell growth directly but activated pancreatic stellate cells. This was followed by immune cell infiltration and acinar-to-ductal metaplasia in Lats1&2 null pancreas. Our RNA seq data revealed several cytokines and chemokine genes, such as ctgf, spp1, cxcl12, cxcl16, were gradually unregulated with time in Lats1&2 null pancreas before immune cell infiltration. Finally, we revealed the phenotype of Lats1&2 DKO mouse was in a YAP1/TAZ-dependent manner. Conclusion and significance: In our present study, our data suggested that deletion of the Lats1&2 genes in acinar cells caused pancreatitis through activation of pancreatic stellate cells directly. Our study discovered a new mechanism of the inflammatory response initiated by pancreatic epithelial cells and regulated by the Hippo signaling pathway, which is likely to be useful for the identification of new strategies for controlling pancreatic inflammation and prevention of pancreatic cancer.
Citation Format: Ming Gao, Jun Liu, Francis E. Sharkey, Howard C. Crawford, Randy L. Johnson, Yidong Chen, Pei Wang. Investigating the novel role of Hippo signaling in mouse pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4087.