bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B11: The MuSiC2 system for discovery and visualization of coding and noncoding cancer drivers
Authors: Wyczalkowski Matthew A. , Bailey Matthew H. , Lou Carolyn , Hu Felix , Chen Justin Y. , Batra Prag , McLellan Michael D. , Ding Li , Wendl Michael C. 
Published: February 2019

Abstract
The MuSiC system has been widely used over the last 5 years by the scientific community for analyzing genomic data across the cancer spectrum. However, the desired scope of analysis has now increased dramatically, due to advances in instrumentation and experimental methods, vastly expanding sample availability, and the general appreciation of many newfound subtleties of the cancer initiation and progression processes themselves. We have extended MuSiC in several ways to address both new requirements and several long-standing issues that have not been manageable with any current analysis system. Here, we focus on three aspects. First, to answer the growing need for noncoding analysis, MuSiC2 extends the common idea of a “significantly mutated gene” model to one of “significantly mutated regions,” including the attendant tasks of interfacing to ENCODE, calculating region-appropriate background mutation rates (BMRs) for hypothesis testing, etc. Second, to address the statistical artifacts realized with most analysis software, we have designed two new filters: one for longer-than-average genes and another for cancer types having elevated BMRs, both scenarios of which typically show appreciably inflated false-positive rates because of upwardly biased passenger mutation counts. Finally, we describe a number of new visualization capabilities designed to give the investigator new interpretive capabilities, including for complex genomic rearrangements that may stem from viral integration. Taken together with improved programmatic efficiencies, the new MuSiC2 system should be useful for discovering and visualizing coding and noncoding cancer drivers in pediatric and adult cancers.
Citation Format: Matthew A. Wyczalkowski, Matthew H. Bailey, Carolyn Lou, Felix Hu, Justin Y. Chen, Prag Batra, Michael D. McLellan, Li Ding, Michael C. Wendl. The MuSiC2 system for discovery and visualization of coding and noncoding cancer drivers [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B11.
Abstract B27: Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib
Authors: Hallberg Bengt , Umapathy Ganseh , Guan Jikui , Gustafsson Dan , Javanmardi Niloufar , Cervantes-Madrid Diana , Djoos Anna , Martinsson Tommy , Palmer Ruth 
Published: February 2019

Abstract
The RAS-RAF-MEK-ERK pathway is a major player in initiation and progression of multiple cancers where it can be hyperactivated by upstream regulatory proteins, such as tyrosine kinases, phosphatases, and GTPases. Several inhibitors targeting the RAS-MAPK pathway exhibit anticancer activity and are approved as single agent in specific cancers. One such is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK, EGFR, and K-RAS mutant lung cancer and neuroblastoma containing hyperactivating RAS-MAPK pathway mutations. In neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations of ALK, NRAS, and NF1 genes, leading to hyperactivation of RAS-MAPK signaling. Targeting the RAS-MAPK pathways offers attractive options for combinatorial treatment together with ALK inhibitors, since monotreatment has not yet produced strong clinical results in ALK-positive neuroblastoma patients. Here we investigate the response of ALK-positive neuroblastoma cell lines to MEK inhibition, employing trametinib. We show that pharmacologic inhibition of the MEK-ERK pathway in ALK-positive neuroblastoma cells results in increased levels of activation/phosphorylation of AKT and ERK5. This feedback response is regulated by the mTORC2 complex protein SIN1. Taken together, our results indicate that blocking MEK-ERK leads to increased activation of AKT signaling core in ALK-positive neuroblastoma, intensifying survival signals in these cells. Our results contraindicate use of MEK inhibitors as an effective single- and polytherapeutic strategy in ALK-positive neuroblastoma.
Citation Format: Bengt Hallberg, Ganseh Umapathy, Jikui Guan, Dan Gustafsson, Niloufar Javanmardi, Diana Cervantes-Madrid, Anna Djoos, Tommy Martinsson, Ruth Palmer. Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B27.
Abstract IA02: Identity shifts in pediatric cancers
Authors: Delattre Olivier , Franzetti G.A. , Laud-Duval K. , Brisac A. , Boeva Valentina , Louis-Brennetot Caroline , Peltier Agathe , Durand Simon , Pierre-Eugène Cécile , Surdez Didier , Lapouble Eve , Pierron Gaelle , Grossetête-Lalami Sandrine , Janoueix-Lerosey Isabelle 
Published: February 2019

Abstract
In contrast to adult cancers, most pediatric malignancies display limited genetic heterogeneity. In Ewing sarcoma, the major driver of tumor development is the expression of the chimeric EWSR1-FLI1 transcription factor, which results from a chromosome translocation. Additional recurrent genetic alterations include the CDKN2A, STAG2, and TP53 genes. Through its binding to specific elements including GGAA microsatellite sequences, EWSR1-FLI1 has a major impact on epigenetic landscape of the cancer cells and consequently, obscures the epigenetic makeup of the Ewing cell-of-origin. The Ewing cell is somehow a “neomorphic” cell, the biologic properties of which are tightly dependent upon the expression level of EWSR1-FLI1. When a cell harbors a low level of expression of EWSR1-FLI1, it loses this neomorphic identity and retrieve its cell-of-origin, mesenchymal phenotype. This leads us to propose a new model of phenotypic plasticity whereby the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential. The causes of EWSR1-FLI1 expression fluctuations are presently unknown. They may be partly stochastic as they are observed in cell lines in vitro but also dependent upon signals from the surrounding microenvironment. The situation is very different in neuroblastoma where the blueprint of the cell-of-origin, most frequently a noradrenergic progenitor, can be clearly detected whatever the genetic abnormalities of the cancer cells. Our recent data nevertheless suggest that neuroblastoma cells may also exhibit some plasticity and transition between different epigenetic states that witness different cell identities. In conclusion, pediatric cancers constitute simplified cancer systems to investigate the relative and interdependent contributions of genetic and nongenetic factors and to document identity shifts.
Citation Format: Olivier Delattre, G.A. Franzetti, K. Laud-Duval, A. Brisac, Valentina Boeva, Caroline Louis-Brennetot, Agathe Peltier, Simon Durand, Cécile Pierre-Eugène, Didier Surdez, Eve Lapouble, Gaelle Pierron, Sandrine Grossetête-Lalami, Isabelle Janoueix-Lerosey. Identity shifts in pediatric cancers [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA02.
Abstract IA10: Neuroblastoma is a biphasic tumor
Authors: Versteeg Rogier , Groningen Tim van , Koster Jan , Valentijn Linda J. , Nes Johan van 
Published: February 2019

Abstract
Neuroblastoma is a pediatric tumor of the peripheral adrenergic lineage, which is neural crest derived. During embryogenesis cells delaminate from the neural crest, migrate ventrally, and differentiate to (nor)-adrenalin producing cells. Neuroblastoma typically expresses differentiation markers of the adrenergic lineage. High-stage neuroblastoma usually goes in complete remission upon therapy but often relapses as resistant disease. Several tumor types were recently found to include phenotypically divergent cell types, resembling lineage development stages. We have found that most neuroblastoma includes two types of tumor cells with shared genomic defects, but highly diverging gene expression profiles. Undifferentiated mesenchymal cells (MES-type) and more differentiated adrenergic cells (ADRN-type) can interconvert and may relate to normal lineage differentiation stages. ChIP-seq analysis of isogenic pairs of MES- and ADRN-type cells revealed distinct, highly consistent super-enhancer landscapes for each cell type. Lineage identity has been proposed to ensue super-enhancer (SE)-associated transcription factor (TF) networks. We identified two SE-associated TF networks that potentially master each cell type. Accordingly, the mesenchymal TF PRRX1 could reprogram the SE- and mRNA-profiles of ADRN-type cells towards an MES-state. Assessment of the clinical relevance of this biphasic system revealed that MES-type cells were more chemoresistant in vitro and were enriched in post-therapy and relapsed tumors. The super enhancer-associated TF networks, probably meant for lineage control in normal development, thus could impose two cellular states of neuroblastoma that shape intratumor heterogeneity.
Citation Format: Rogier Versteeg, Tim van Groningen, Jan Koster, Linda J. Valentijn, Johan van Nes. Neuroblastoma is a biphasic tumor [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA10.
Abstract IA18: MYCN amplification and ATRX mutations are incompatible in neuroblastoma
Authors: Zeineldin Maged , Federico Sara , Chen Xiang , Xu Beisi , Stewart Elizabeth , Naranjo Arlene , Hogarty Michael D. , Dyer Michael A. 
Published: February 2019

Abstract
Age and stage of disease at diagnosis are associated with outcome in neuroblastoma. A previous study identified ATRX point mutations and in-frame deletions in older patients with stage 4 disease. To validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables, we collaborated with the Children’s Oncology Group and sequenced the entire ATRX genomic locus in 475 neuroblastoma tumor samples to validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables. Older age at diagnosis, stage 4 disease, and unfavorable histology were significantly associated with mutations in the ATRX gene; MYCN amplification was mutually exclusive from ATRX mutations. To directly test if ATRX mutations and MYCN amplification are incompatible in neuroblastoma, we mutated the ATRX gene in MYCN amplified neuroblastoma cell lines and ectopically expressed MYCN in ATRX mutant neuroblastoma cell lines. Both approaches showed that ATRX and MYCN amplification are incompatible in neuroblastoma in culture and in vivo. To gain a better understanding of the underlying molecular and cellular mechanisms of this incompatibility, we performed a series of experiments including telomere analysis, epigenetic profiling, electron microscopic analysis of dying cells, and metabolic profiling. We discovered that induction of MYCN expression in ATRX mutant neuroblastoma cells leads to metabolic reprogramming, mitochondrial dysfunction, increased reactive oxygen species, and replicative stress. We propose that this leads to synthetic lethality in ATRX mutant neuroblastomas because of the underlying replicative stress in those cells as a result of dysfunction of this essential histone chaperone complex.
Citation Format: Maged Zeineldin, Sara Federico, Xiang Chen, Beisi Xu, Elizabeth Stewart, Arlene Naranjo, Michael D. Hogarty, Michael A. Dyer. MYCN amplification and ATRX mutations are incompatible in neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA18.
Abstract IA23: Metabolic complexity in cancer cells and tumors
Authors: DeBerardinis Ralph J. 
Published: February 2019

Abstract
Metabolism is dynamic and responds to a wide range of cell-intrinsic and cell-extrinsic factors. In cancer, cell-intrinsic influences on metabolism include somatically acquired mutations in oncogenes and tumor suppressor genes, many of which regulate metabolic activity. Cell-extrinsic factors include nutrient access, which may become limiting due to inadequate vasculature and intense fuel utilization, and metabolic interactions with stromal and immune cells. A major challenge in cancer metabolism research is to understand how these various factors culminate in the metabolic phenotype of an intact tumor, and ultimately to identify which altered pathways represent potential therapeutic targets. We have taken two parallel approaches to understand metabolic complexity in human cancer. The first uses a combination of multiparametric imaging and intraoperative stable isotope infusions to assess metabolic fluxes in patients with solid tumors, and to compare fluxes between tumors and adjacent benign tissue. Genomic, histologic, and metabolic analysis of tumor samples allows us to correlate various intrinsic and extrinsic factors to specific aspects of the metabolic phenotype. The second approach uses standardized culture conditions to assess cell-intrinsic heterogeneity of metabolic preferences and dependencies in large panels of human cancer cell lines. This approach has uncovered liabilities associated with specific molecular subtypes of non-small cell and small cell lung cancer. I will discuss the application of these two approaches to metabolic heterogeneity in human cancer, with an emphasis on features relevant to intact tumors and therapeutic liabilities.
Citation Format: Ralph J. DeBerardinis. Metabolic complexity in cancer cells and tumors [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA23.
Abstract PR09: Cancer-specific retargeting of BAF complexes by a prion-like domain
Authors: Boulay Gaylor , Sandoval Gabriel J. , Riggi Nicolo , Iyer Sowmya , Buisson Rémi , Naigles Beverly , Awad Mary E. , Rengarajan Shruthi , Volorio Angela , McBride Matthew J. , Broye Liliane C. , Zou Lee , Stamenkovic Ivan , Kadoch Cigall , Rivera Miguel N. 
Published: February 2019

Abstract
Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here we show that the BAF chromatin-remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.
Citation Format: Gaylor Boulay, Gabriel J. Sandoval, Nicolo Riggi, Sowmya Iyer, Rémi Buisson, Beverly Naigles, Mary E. Awad, Shruthi Rengarajan, Angela Volorio, Matthew J. McBride, Liliane C. Broye, Lee Zou, Ivan Stamenkovic, Cigall Kadoch, Miguel N. Rivera. Cancer-specific retargeting of BAF complexes by a prion-like domain [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR09.
Abstract A002: Comparison of circulating microRNAs in plasma before and after radical prostatectomy among men treated for prostate cancer
Authors: McDonald Alicia C. , Raman Jay D. , Shen Jing , Liao Jason , Vira Manish 
Published: February 2019

Abstract
Introduction: MicroRNAs (miRNAs) have been linked to advanced prostate cancer; however, their role as circulating biomarkers of prostate cancer (PC) status has yet to be determined. We examined whether circulating miRNAs in plasma could be employed as biomarkers of disease among men treated for PC by radical prostatectomy (RP).
Methods: Men with clinically localized PC scheduled for a RP were recruited. Demographics, medical history, clinical information, pre-RP blood, and post-RP blood within 1 year after RP were collected. Pre- and post-RP blood were processed into plasma and the expression of the 16 most statistically significant PC circulating miRNAs in plasma identified from our previous study (miR- 381, 34a, 523, 365, 122, 375, 1255b, 34b, 450b-5p, 639, 885-5p, 1260, 150, 378, 671-3p, 148a) were examined using real-time PCR. Wilcoxon signed ranked test was used to compare the median expression of these miRNAs between pre- and post-RP plasma.
Results: There were 29 men, aged 43 to 77 years, included. Majority were white men (79.3%). The median preoperative serum PSA was 6.3 ng/mL. Majority had a pathologic Gleason score of 7 (3+4) (56%) and a pathologic tumor stage of T3 (60.7%). There was no statistically significant difference in miRNA expression between pre- and post-RP plasma.
Conclusion: No difference in miRNA expression before and immediately after RP was observed, possibly due to the lack of impact of tumor removal on miRNA expression and the timing of plasma collections. Future studies that examine post-RP plasma miRNA expression over time with PC recurrence are warranted.
Citation Format: Alicia C. McDonald, Jay D. Raman, Jing Shen, Jason Liao, Manish Vira. Comparison of circulating microRNAs in plasma before and after radical prostatectomy among men treated for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A002.
Abstract A016: KDM4B promotes castration-resistant prostate cancer by regulating alternative splicing of the androgen receptor
Authors: Liu Zhi-Ping 
Published: February 2019

Abstract
Emergence of constitutively active androgen receptor variant AR-V7 is associated with poor survival of castration-resistant prostate cancer (CRPC). AR-V7 can be generated by the inclusion of cryptic exon CE3 via alternative splicing, but the mechanism of AR-V7 activation remains elusive. Here, we show that histone lysine demethylase KDM4B promotes CRPC via generation of AR-V7. Genetic inactivation of KDM4B in CRPC cells suppressed xenograft growth and abolished tumor AR-V7 expression. Pharmacologic inhibition of KDM4B inhibited tumor growth and sensitized CRPC cells to current antiandrogen therapy. Mechanistically, KDM4B promotes AR-V7 as a trans-acting splicing factor and couples the spliceosome to the chromatin. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC.
Citation Format: Zhi-Ping Liu. KDM4B promotes castration-resistant prostate cancer by regulating alternative splicing of the androgen receptor [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A016.
Abstract A019: Heme-oxygenase 1 drives the metabolic fate in prostate cancer
Authors: Arciuch Valeria G. Antico , Cascardo Florencia , Velazquez Florencia , Vickers Sofia Lage , Anselmino Nicolas , Labanca Estefania , Cotignola Javier , Gueron Geraldine , Navone Nora , Vazquez Elba 
Published: February 2019

Abstract
Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Energetic metabolism alterations have become a new hallmark of cancer, since variations in a single gene can orchestrate changes in metabolic pathways and confer an adaptive advantage. Heme-oxygenase 1 (HO-1) exerts an antitumoral role in PCa inhibiting cell proliferation, migration, tumor growth, and angiogenesis. The aim of this work was to assess the role of HO-1 in the metabolic signature of PCa.
Through RNA-Seq we found a set of metabolic genes deregulated under pharmacologic induction (hemin treatment) or genetic induction of HO-1 in PC3 cells. STAR and ATP5L2 were upregulated, while HMGCS2, PRODH, and ACOT12 were downregulated. These genes encode for steroid hormone metabolism, ATP synthesis, ketogenesis, proline and lipid metabolism. The analysis of the deregulated genes (2-fold) by Gene Ontology revealed alterations in several metabolic pathways such as steroid, proline and lipid metabolism, and ATP synthesis. Functional analysis highlighted a decrease in oxygen consumption rate and ATP production under hemin treatment. Furthermore, HO-1 induction led to a decrease in the extracellular lactate levels.
Bone is the only site of PCa progression, and bone cells are able to produce factors that favor progression. However, the molecular nature of this interaction remains elusive. Our results performed on cocultures of PC3 cells (treated or not with hemin) with Raw264.7 (preosteoclastic) or MC3T3 (preosteoblastic) cells demonstrate that HO-1 directs the metabolic fate of bone precursor cells due to the deregulation of glycolytic genes. HO-1 induction in PC3 cells downregulated PKM2 and LDHA expression in cocultured Raw264.7 and MC3T3 cells (p&lt; 0.05).
Based on our results, we propose HO-1 as a key regulator of the metabolic status of PCa cells and a powerful mediator capable of redefining the metabolic signature of bone precursor cells, thus favoring the establishment of a less aggressive phenotype.
Citation Format: Valeria G. Antico Arciuch, Florencia Cascardo, Florencia Velazquez, Sofia Lage Vickers, Nicolas Anselmino, Estefania Labanca, Javier Cotignola, Geraldine Gueron, Nora Navone, Elba Vazquez. Heme-oxygenase 1 drives the metabolic fate in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A019.