bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 205: Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies
Authors: Russo Mariangela , Lamba Simona , Lorenzato Annalisa , Sogari Alberto , Corti Giorgio , Rospo Giuseppe , Montone Monica , Lazzari Luca , Arena Sabrina , Oddo Daniele , Linnebacher Michael , Sartore-Bianchi Andrea , Pietrantonio Filippo , Siena Salvatore , Nicolantonio Federica Di , Bardelli Alberto 
Published: August 2018

Abstract
Clinical effectiveness of targeted therapies is often transitory and virtually all patients develop secondary resistance. The heterogeneous mechanisms of resistance and the sub-clonal evolution pattern of cell populations that emerge upon pharmacological selection limit disease control with subsequent lines of therapy. We used colorectal cancer (CRC) to test the hypothesis that ancestral oncogenic event (such as WNT pathway alterations) shared by every cell sub-clone might be better suited as therapeutic targets than heterogeneous events in the branches, as the former remain present in each drug-resistant cell independently from its genetic drift.To test our assumption, we first generated a panel of CRC cells resistant to commonly used targeted agents, including EGFR and BRAF inhibitors. Treatment with targeted therapies, although initially effective, fuels clonal evolution and further amplifies molecular diversity. Exome sequencing and phylogenetic tracking unveiled a complex sub-clonal architecture in CRC resistance cell populations, indicating parallel evolution of multiple independent cellular lineages, associated with distinct genomic landscapes.Functional and pharmacological modulation of WNT signaling induces cell death in CRC preclinical models from patients that relapsed during treatment, regardless of drug type or resistance mechanisms. Pharmacological blockade of WNT ligands secretion resulted in translocation of β-catenin from the cytoplasm and nucleus to the plasma membrane, decreased of β-catenin dependent Tcf/LEF transcriptional activity, and cell growth impairment despite massive molecular drift of resistant derivatives. Concomitant blockade of WNT and MAPK signalling restrained evolution of drug-resistant clones.In summary, reliance of CRC on the WNT pathway is preserved in later phases of colorectal carcinogenesis when tumors face genomic bottlenecks and sub-clonal evolution driven by administration of target therapies; thus offering the possibility of a common therapeutic strategy to overcome secondary resistance to treatments.
Citation Format: Mariangela Russo, Simona Lamba, Annalisa Lorenzato, Alberto Sogari, Giorgio Corti, Giuseppe Rospo, Monica Montone, Luca Lazzari, Sabrina Arena, Daniele Oddo, Michael Linnebacher, Andrea Sartore-Bianchi, Filippo Pietrantonio, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli. Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies [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 205.
Abstract 2051: Perfusable 3D angiogenesis in a high-throughput microfluidic culture platform
Authors: Bircsak K M. , Duinen V van , Trietsch S J. , Zonneveld A J. van , Hankemeier T , Saleh A , Vulto P 
Published: August 2018

Abstract
The transition from 2D to 3D cell culture is a first step towards more physiologically relevant in vitro cancer models. To adequately capture the complex tissue architectures observed in vivo, 3D microfluidic techniques incorporate and achieve long-term gradient stability, continuous perfusion and patterning of cancer cell layers as stratified co-cultures. We used a standardized high-throughput (n=40) microfluidic 3D tissue culture platform called the OrganoPlate® to generate precisely controlled gradients, without pumps, ideal for growing blood vessels and inducing controlled 3D angiogenic sprouting. The blood vessel is grown against an extracellular matrix (ECM) gel with cancer cells and is subsequently exposed to pro- and antiangiogenic compounds to direct sprouting towards 3D cancer cell clusters. Utilizing high-content confocal time-lapse imaging and analysis, angiogenic potential was measured in various cancer models. The exposed vasculature shows many of the important hallmarks of cancer angiogenesis found in vivo, including tip cells induction and migration and stalk cells formation. Importantly, the stalk cells develop a perfusable lumen that is connected to the parental vessel as demonstrated with perfusion of high-molecular-weight (150KD) fitc-dextran through microvascular structures. This model will be used as an in vitro cancer screening platform to unravel the important drivers in angiogenesis and vasculogenesis and the mechanism of action of antiangiogenic compounds. By combining this culture platform with mural cells, cell-cell interactions can be studied. In parallel, we will combine this 3D cancer angiogenesis platform with our current Tumor-on-a-Chip models to create tissue models with integrated vasculature.
Citation Format: K M. Bircsak, V van Duinen, S J. Trietsch, A J. van Zonneveld, T Hankemeier, A Saleh, P Vulto. Perfusable 3D angiogenesis in a high-throughput microfluidic culture platform [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 2051.
Abstract 2069: Therapeutic targeting of ependymoma as informed by oncogenic enhancers
Authors: Mack Stephen C. , Excellence Global Ependymoma Network of 
Published: August 2018

Abstract
Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas commonly resist chemotherapy and lack available targeted agents for clinical trial development. In the case of genomically balanced ependymomas, and those driven by fusion oncoproteins, we hypothesized that the chromatin landscapes could uncover oncogenes that would inform actionable targets for therapy and reveal specific transcriptional circuitries to identify molecular origins of the disease. We therefore interrogated the oncogenic drivers of ependymoma by characterizing the active regulatory landscapes of 42 primary tumors through an integrative analysis of H3K27ac ChIP-seq, RNA-seq, whole-exome sequencing (WES), whole genome sequencing (WGS), copy number profiling, and DNA methylation profiling. Across the landscape of ependymal tumors, enhancer mapping revealed putative oncogenes, including NFIX, MIRLET7BHG, FGFR1, WEE1, and MTSS1L, and delineated subgroup specific enhancer lesions. Reconstruction of enhancer networks permitted the identification of core transcription factors (TFs) that establish ependymoma cell state, and lineage-specifying TFs that dictate molecular subgroup identity. Lineage-associated TFs point to distinct spatio-temporal origins of ependymoma subgroups such as FOXJ1 TF activity and expression observed preferentially in subsets of hindbrain ependymomas. To translate our results into a potential clinical paradigm, we demonstrate cancer dependencies on super enhancer associated genes and lineage TFs, and establish the utility of chromatin landscape analysis to predict novel targets for cancer therapy.
Citation Format: Stephen C. Mack, Global Ependymoma Network of Excellence. Therapeutic targeting of ependymoma as informed by oncogenic enhancers [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 2069.
Abstract 2078: Analysis of DNA structural variations in context of the gene regulatory landscape of pediatric ALL
Authors: Oksa Laura , Vouttilainen Miikka , Vuorenmaa Tapio , Laukkanen Saara , Lahnalampi Mari , Lohi Olli , Heinäniemi Merja 
Published: August 2018

Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric leukemia. It comprises of multiple subtypes with combinations of chromosomal rearrangements, indels and copy number variations. Furthermore, there is a significant number of somatic mutations located outside of protein coding regions of the genome. These DNA alterations can be classified based on whether they 1) introduce novel transcription factor binding sites, 2) create aberrant (super-)enhancers, or 3) lead to the loss of regulatory boundaries at oncogene loci upon disruption of CTCF binding sites.
We performed whole genome sequencing (WGS) on two T-ALL and 16 pre-B ALL patients from diagnostic and remission samples, and measured transcriptional activity using Global Nuclear Run-on sequencing (GRO-seq). These results were integrated with chromatin topology information and transcript annotations to yield comprehensive characterization of the gene regulatory landscape. The effect on gene expression was further analyzed based on monoallelic expression.
Altogether, we found 49 translocations, 153 deletions, 9 duplications and 22 inversions across the pre-B ALL samples. Majority of the changes were located within the annotated gene regions. At 25 of these 233 sites, we found evidence that active enhancers resulted in transcription-coupled genetic instability at DNA breakpoints. In a pre-B ALL case, our analysis successfully captured complex translocation event involving ETV6 (ETV6-MUTYH, ETV6-chr7, ETV6-chr21, ETV6-TXNRD2), and deletion at chr22 that hit to active promoters of PATZ1 and DRG1 genes leading to monoallelic expression of these genes.
In T-ALLs, we found 13 translocations (8 intergenic) and 9 deletions. In a T-ALL case, we found that translocation between TCR-beta locus and chr9 brought an active promoter to the proximity of TMEM38B resulting in increased gene expression. We also found a deletion in active promoter at chr9 leading to decreased expression of MTAP and CDKN2A genes. Moreover, a large deletion in chr11 brought oncogenic transcription factor LMO2 and RAG1 close to each other.
In summary, we present a genome-wide approach to link structural variation events with gene regulatory features in ALL cells. This extends previous approaches that have mainly focused on genetic changes at coding regions.
Citation Format: Laura Oksa, Miikka Vouttilainen, Tapio Vuorenmaa, Saara Laukkanen, Mari Lahnalampi, Olli Lohi, Merja Heinäniemi. Analysis of DNA structural variations in context of the gene regulatory landscape of pediatric ALL [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 2078.
Abstract 208: Multi-omics analysis in primary cell cultures reveals the genomic basis of phenotypic diversity within tumors
Authors: Liu Sixue , Yang Zuyu , Li Guanghao , Luo Yanting , Gong Qiang , Wu Xin , Li Tao , Zhang Zhiqian , Xing Baocai , Xu Xiaolan , Lu Xuemei 
Published: August 2018

Abstract
To uncover the functionally essential variations related to tumorigenesis and tumor progression from large amount of cancer genomics data is still challenging due to the genetic diversity between patients, and extensive inter- and intra-tumor heterogeneity at the genomic, epigenomic, and transcription levels. Multiple primary cultures derived from phenotypically distinct subpopulations of a single patient may not only represent the diversity and heterogeneity of tumor cell types and states (such as metastasis and drug-resistant), but also narrow the analysis in genomic basis of phenotypic diversity down to the relatively small
number of variations between subpopulations with the same genetic background. Performing multi-omics sequencing, we identified variations in single nucleotide, copy number, DNA methylation and gene expression among four primary cell cultures from primary and recurrent tumors in a hepatocellular carcinoma patient. We observed the discrepancy between the phylogenetic relationships revealed by single nucleotide variations (SNVs) and transcriptional profiles in the four cell cultures. The differences in gene expression, which indicated the distinct cellular characteristics and tumorigenic capability in one of the two recurrent cell clones, were correlated to the copy number alterations (CNAs) and DNA methylation variation in gene body and confirmed by the characterization of cellular phenotype. Our multi-omics analysis in heterogeneous clones derived from an individual revealed that CNAs and epigenomic changes, rather than SNVs, dominantly contribute to the phenotypic diversity among subpopulations in tumors, which could shed light on developing new cancer diagnosis and treatment strategies based on gene dosage and epigenetic modification
Citation Format: Sixue Liu, Zuyu Yang, Guanghao Li, Yanting Luo, Qiang Gong, Xin Wu, Tao Li, Zhiqian Zhang, Baocai Xing, Xiaolan Xu, Xuemei Lu. Multi-omics analysis in primary cell cultures reveals the genomic basis of phenotypic diversity within tumors [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 208.
Abstract 2080: Role of differentially expressed micro RNAs in non-WNT, non-SHH medulloblastoma
Authors: Paul Raikamal , Jalali Rakesh , Sridhar Epari , Moiyadi Aliasagar , Shirsat Neelam 
Published: August 2018

Abstract
Medulloblastoma is a common malignant brain tumor in children. It has four distinct molecular subgroups namely WNT, SHH, Group 3 and Group 4. The molecular subgroups differ in their clinical characteristics including age, incidence of metastasis and survival. Group 3 and Group 4 medulloblastomas have overlapping gene expression profile but are distinct in their clinical behavior. Group 3 medulloblastomas have the worst overall survival rates whereas Group 4 medulloblastomas have intermediate survival. Group 3 and Group 4 tumors are not associated with any known signaling pathway and due to their overlapping expression profiles it is often difficult to accurately identify the subgroup, which is very crucial for the appropriate treatment design. MiR-592, located in the intronic region of GRM8 gene, is over expressed in Group 4 medulloblastoma along with its host gene, thus acting as a good marker for Group 4 tumors. MiR-204, on the other hand is expressed from the 6th intron of TRPM3 gene and expressed in some Group 3 and majority of Group 4 medulloblastomas. In order to delineate the role of miR-592 and miR-204 in medulloblastoma biology, effect of expression of these microRNAs on medulloblastoma cell growth and behavior were investigated. The micro RNAs were expressed in a lentiviral mediated inducible manner in Group 3 medulloblastoma cell lines D283, D425 and D341 and their effects on cell proliferation, anchorage-independent growth and invasion potential were studied. MiR-592 expression had marginal effects on the anchorage independent growth potential and the tumorigenic potential of the Group 3 cell line where as miR-204 expression led to significant decrease in the anchorage independent growth, tumorigenic potential, as well as invasion potential of the medulloblastoma cell lines. Further in order to decipher the molecular mechanisms underlying these micro RNA mediated effects, RNA-sequencing analysis of miR-592 and miR-204 expressing medulloblastoma cells were performed to identify genes that are differentially expressed upon micro RNA expression. The results helped us to identify the molecular pathways that are being affected by the micro RNA expression and how they affect the malignant behavior of medulloblastoma cells.
Citation Format: Raikamal Paul, Rakesh Jalali, Epari Sridhar, Aliasagar Moiyadi, Neelam Shirsat. Role of differentially expressed micro RNAs in non-WNT, non-SHH medulloblastoma [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 2080.
Abstract 2082: High-throughput droplet digital PCR for MYCN amplification detection in FFPE neuroblastoma samples: Cost-effective, rapid, feasible, and reliable alternative to FISH
Authors: Somasundaram Dinesh Babu , Aravindan Sheeja , Yu Zhongxin , Jayaraman Muralidharan , Tran Ngoc TB , Li Shibo , Herman Terence , Aravindan Natarajan 
Published: August 2018

Abstract
MYCN amplification directly correlates with the clinical course of neuroblastoma (NB) and poor patient survival, and serves as the most critical negative prognostic marker. Although FISH remains the gold standard for clinical diagnosis of MYCN status in NB, its limitations warrant the identification of rapid, reliable, less technically challenging, and inexpensive alternate approaches. In the present study, we examined the concordance of droplet digital PCR (ddPCR, in combination with IHC) with FISH for MYCN detection in FFPE NB samples. In 112 NB cases, ddPCR analysis demonstrated a 96-100% concordance with FISH. Consistently, IHC grading revealed 92-100% concordance with FISH. Comparing ddPCR with IHC, we observed a concordance of 95-98%. The results demonstrate that MYCN amplification status in NB cases can be assessed with ddPCR, and suggest that ddPCR could be a technically less challenging method of detecting MYCN status in FFPE specimens. More importantly, these findings illustrate the concordance between FISH and ddPCR in the detection of MYCN status. Together, the results suggest that rapid, less technically demanding, and inexpensive ddPCR in conjunction with IHC could serve as an alternate approach to detect MYCN status in NB cases, with near-identical sensitivity to that of FISH.
Funding: NIH 1P20GM103639-01 from the COBRE Program of NIH; OUHSC Department of Radiation Oncology Research Development funds
Citation Format: Dinesh Babu Somasundaram, Sheeja Aravindan, Zhongxin Yu, Muralidharan Jayaraman, Ngoc TB Tran, Shibo Li, Terence Herman, Natarajan Aravindan. High-throughput droplet digital PCR for MYCN amplification detection in FFPE neuroblastoma samples: Cost-effective, rapid, feasible, and reliable alternative to FISH [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 2082.
Abstract 2106: Focal gene expression profiling of counterstained FFPE with correlation to morphology using TempO-Seq
Authors: Imler Elliot , Babic Milos , Adams Deanna , Shepard Peter , Yeakley Joanne , Nagle Raymond B. , Seligmann Bruce 
Published: August 2018

Abstract
We previously reported on use of the whole transcriptome TempO-Seq® assay to profile gene expression from 1 mm2 focal areas of 5 µm thick FFPE sections of normal and cancerous tissue to identify disease biomarkers and mechanistic pathways. We are now presenting data demonstrating that the TempO-Seq assay can be performed as an “in situ” assay on slides by an automated slide stainer, followed by counterstaining. Then, using an automated digital imaging platform, areas as small as 30 μm in diameter within the FFPE section can be profiled, permitting the gene expression data to be correlated directly to the specific morphology of that focal area. The pathologist uses a computer interface to select areas for profiling during the course of the histologic examination of the section, and then the TempO-Seq probes are automatically recovered from those region(s) of interest. After depositing them into PCR tubes, the assay is completed with PCR amplification and sample barcoding before pooling the samples into a library for sequencing. Analysis of the sequencing data is carried out automatically to report results. There is no use of laser capture or destruction of the tissue. The TempO-Seq processed slides can be archived and additional areas may be sampled at a later date. In this study, we sample replicate areas of matched normal vs. cancerous tissue, measuring gene biomarkers of clinical utility, gene fusions, and SNPs. We present gene expression profiles for replicate areas of pure stroma, single normal glands, single high-grade PIN glands, and single cancerous glands from prostate FFPE, demonstrating the statistical power of the TempO-Seq in situ assay as well as the correlation to focal histology and the use of focal differential expression to elucidate molecular pathways involved in the transition from normal tissue to cancer. We report measurements of clinically relevant biomarkers and signatures from clinical FFPE samples, plus therapeutic targets and drug resistance genes. This new approach demonstrates that complex molecular tests can be carried out by any pathologist in their own lab, and makes moot the issues of “% cancer” and amount of tissue required for testing. The approach we present brings extraction-free complex molecular testing of FFPE into the pathology lab and takes molecular pathology to a new level of simplicity, focal precision and correlation to morphology.
Citation Format: Elliot Imler, Milos Babic, Deanna Adams, Peter Shepard, Joanne Yeakley, Raymond B. Nagle, Bruce Seligmann. Focal gene expression profiling of counterstained FFPE with correlation to morphology using TempO-Seq [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 2106.