33 results on '"Dirks, Peter"'
Search Results
2. Glioma Stem Cell Lines Expanded in Adherent Culture Have Tumor-Specific Phenotypes and Are Suitable for Chemical and Genetic Screens.
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Pollard, Steven M., Yoshikawa, Koichi, Clarke, Ian D., Danovi, Davide, Stricker, Stefan, Russell, Roslin, Bayani, Jane, Head, Renee, Lee, Marco, Bernstein, Mark, Squire, Jeremy A., Smith, Austin, and Dirks, Peter
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GLIOMAS ,CELLULAR immunity ,CANCER cell proliferation ,BRAIN tumors ,SEROTONIN ,STEM cells ,GENETICS - Abstract
Human brain tumors appear to have a hierarchical cellular organization suggestive of a stem cell foundation. In vitro expansion of the putative cancer stem cells as stable cell lines would provide a powerful model system to study their biology. Here, we demonstrate routine and efficient derivation of adherent cell Iines from malignant glioma that display stem cell properties and initiate high-grade gliomas following xenotransplantation. Significantly, glioma neural stem (GNS) cell lines from different tumors exhibit divergent gene expression signatures and differentiation behavior that correlate with specific neural progenitor subtypes. The diversity of gliomas may, therefore, reflect distinct cancer stem cell phenotypes. The purity and stability of adherent GNS cell lines offer significant advantages compared to "sphere" cultures, enabling refined studies of cancer stem cell behavior. A proof-of-principle live cell imaging-based chemical screen (450 FDA-approved drugs) identifies both differential sensitivities of GNS cells and a common susceptibility to perturbation of serotonin signaling. [ABSTRACT FROM AUTHOR]
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- 2009
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3. Cancer and Stem Cell Biology: How Tightly Intertwined?
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Kim, Carla F. and Dirks, Peter B.
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STEM cells ,CANCER cells ,CANCER ,CONFERENCES & conventions - Abstract
Ever since the discovery of cancer stem cells in leukemia and, more recently, in solid tumors, enormous attention has been paid to the apparent stem cell nature of cancer. These concepts were the focus of the "Stem Cells and Cancer" symposium held recently at the University of California, San Francisco, and the inspiration for this overview of current research and important questions emerging in this area. [ABSTRACT FROM AUTHOR]
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- 2008
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4. Brain Cancer Stem Cells: A Level Playing Field.
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Pollard, Steven, Clarke, lan D., Smith, Austin, and Dirks, Peter
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LETTERS to the editor ,STEM cell research - Abstract
A response by Steven Pollard and colleagues to a letter to the editor about their article on the study of brain cancer stem cells.
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- 2009
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5. MicroRNAs and Parallel Stem Cell Lives
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Dirks, Peter B.
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STEM cells , *NON-coding RNA , *EPITHELIAL cells , *CELL populations , *BREAST tumors , *CELL differentiation , *CANCER cells - Abstract
A new study by demonstrates that certain microRNAs that regulate the self-renewal factor BMI1 are downregulated in purified populations of normal mammary epithelial stem cells and breast tumor-initiating cells. These findings have important implications for the regulation of self-renewal and differentiation by microRNAs and suggest new ways of targeting cancer stem cells. [ABSTRACT FROM AUTHOR]
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- 2009
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6. High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities.
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Hart, Traver, Chandrashekhar, Megha, Aregger, Michael, Steinhart, Zachary, Brown, Kevin R., MacLeod, Graham, Mis, Monika, Zimmermann, Michal, Fradet-Turcotte, Amelie, Sun, Song, Mero, Patricia, Dirks, Peter, Sidhu, Sachdev, Roth, Frederick P., Rissland, Olivia S., Durocher, Daniel, Angers, Stephane, and Moffat, Jason
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CRISPRS , *GENOTYPES , *ONCOGENIC proteins , *RNA , *TARGETED drug delivery , *PHYSICAL fitness - Abstract
Summary The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell. [ABSTRACT FROM AUTHOR]
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- 2015
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7. Functional Enhancers Shape Extrachromosomal Oncogene Amplifications.
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Morton, Andrew R., Dogan-Artun, Nergiz, Faber, Zachary J., MacLeod, Graham, Bartels, Cynthia F., Piazza, Megan S., Allan, Kevin C., Mack, Stephen C., Wang, Xiuxing, Gimple, Ryan C., Wu, Qiulian, Rubin, Brian P., Shetty, Shashirekha, Angers, Stephane, Dirks, Peter B., Sallari, Richard C., Lupien, Mathieu, Rich, Jeremy N., and Scacheri, Peter C.
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EXTRACHROMOSOMAL DNA , *GENE amplification , *NON-coding DNA , *CIRCULAR DNA , *ONCOGENES , *CELL proliferation - Abstract
Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome. • Enhancers active in the cell of origin are co-amplified with oncogenes • Circular extrachromosomal amplicons are associated with enhancer rewiring • Endogenous and new enhancers on amplicons contribute to cell proliferation • Skewed co-amplification that selects enhancers is found across several tumor types Extrachromosomal oncogene amplification is a common occurrence across a broad range of cancers, yet the chromatin landscape of these high-level amplifications is poorly understood. Using a combination of approaches to explore their chromatin topology and enhancer landscape, Morton et al. observed that these oncogene amplifications are shaped by regulatory dependencies in the non-coding genome. [ABSTRACT FROM AUTHOR]
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- 2019
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8. A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression.
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Chen, Xin, Wanggou, Siyi, Bodalia, Ankur, Zhu, Min, Dong, Weifan, Fan, Jerry J., Yin, Wen Chi, Min, Hyun-Kee, Hu, Malini, Draghici, Diana, Dou, Wenkun, Li, Feng, Coutinho, Fiona J., Whetstone, Heather, Kushida, Michelle M., Dirks, Peter B., Song, Yuanquan, Hui, Chi-chung, Sun, Yu, and Wang, Lu-Yang
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ION channels , *GLIOMAS , *MITOSIS regulation , *DROSOPHILA , *TISSUE mechanics - Abstract
Summary Alteration of tissue mechanical properties is a physical hallmark of solid tumors including gliomas. How tumor cells sense and regulate tissue mechanics is largely unknown. Here, we show that mechanosensitive ion channel Piezo regulates mitosis and tissue stiffness of Drosophila gliomas, but not non-transformed brains. PIEZO1 is overexpressed in aggressive human gliomas and its expression inversely correlates with patient survival. Deleting PIEZO1 suppresses the growth of glioblastoma stem cells, inhibits tumor development, and prolongs mouse survival. Focal mechanical force activates prominent PIEZO1-dependent currents from glioma cell processes, but not soma. PIEZO1 localizes at focal adhesions to activate integrin-FAK signaling, regulate extracellular matrix, and reinforce tissue stiffening. In turn, a stiffer mechanical microenvironment elevates PIEZO1 expression to promote glioma aggression. Therefore, glioma cells are mechanosensory in a PIEZO1-dependent manner, and targeting PIEZO1 represents a strategy to break the reciprocal, disease-aggravating feedforward circuit between tumor cell mechanotransduction and the aberrant tissue mechanics. Video Abstract Highlights • Drosophila Piezo regulates cell proliferation and tissue stiffening of gliomas • Human PIEZO1 is overexpressed in aggressive gliomas and predicts poor survival • Piezo/PIEZO1 interacts with integrin-FAK signaling to regulate tumor stiffness • PIEZO1 co-opts aberrant tissue mechanics to promote glioma aggression PIEZO1 is an ion channel that converts mechanical stimuli into cellular signaling. Here, Chen et al. perform multi-species studies to define a feedforward circuit mediated by PIEZO1 and tumor tissue mechanics to promote glioma growth. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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9. Protocol for the derivation of primary cancer stem cell lines from human ependymal tumors.
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Richman CM, Dirks PB, Taylor MD, and Michealraj KA
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Cancer stem cells (CSCs) established from surgical biopsies closely mimic the human context and can be used to investigate disease mechanisms, genetic fitness, and therapeutic evaluation. Here, we present a protocol for the derivation of primary patient-derived CSC lines from ependymal tumors. We describe the necessary steps, from surgical intervention and biopsy to the dissociation of ependymomas to derive cultures. We then detail procedures for cell line propagation and define the characteristics of these primary cancer cell lines. For complete details on the use and execution of this protocol, please refer to Michealraj et al.
1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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10. Early rhombic lip Protogenin +ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.
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Visvanathan A, Saulnier O, Chen C, Haldipur P, Orisme W, Delaidelli A, Shin S, Millman J, Bryant A, Abeysundara N, Wu X, Hendrikse LD, Patil V, Bashardanesh Z, Golser J, Livingston BG, Nakashima T, Funakoshi Y, Ong W, Rasnitsyn A, Aldinger KA, Richman CM, Van Ommeren R, Lee JJY, Ly M, Vladoiu MC, Kharas K, Balin P, Erickson AW, Fong V, Zhang J, Suárez RA, Wang H, Huang N, Pallota JG, Douglas T, Haapasalo J, Razavi F, Silvestri E, Sirbu O, Worme S, Kameda-Smith MM, Wu X, Daniels C, MichaelRaj AK, Bhaduri A, Schramek D, Suzuki H, Garzia L, Ahmed N, Kleinman CL, Stein LD, Dirks P, Dunham C, Jabado N, Rich JN, Li W, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Millen KJ, Ellison DW, Dimitrov DS, and Taylor MD
- Abstract
We identify a population of Protogenin-positive (PRTG
+ve ) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ , a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB., Competing Interests: Declaration of interests The authors declare no competing interests. A patent related to this work was submitted by University of Pittsburgh (University Docket No. 05700/F&R ref. 48881-0028P01), US 63/275,326, “Molecules that bind to Protogenin polypeptides.”, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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11. Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity.
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Chen X, Momin A, Wanggou S, Wang X, Min HK, Dou W, Gong Z, Chan J, Dong W, Fan JJ, Xiong Y, Talipova K, Zhao H, Chen YX, Veerasammy K, Fekete A, Kumar SA, Liu H, Yang Q, Son JE, Dou Z, Hu M, Pardis P, Juraschka K, Donovan LK, Zhang J, Ramaswamy V, Selvadurai HJ, Dirks PB, Taylor MD, Wang LY, Hui CC, Abzalimov R, He Y, Sun Y, Li X, and Huang X
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- Mice, Animals, Endothelial Cells metabolism, Brain metabolism, Ion Channels metabolism, Blood-Brain Barrier metabolism, beta Catenin metabolism, beta Catenin therapeutic use, Brain Neoplasms drug therapy, Brain Neoplasms pathology
- Abstract
Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2
+ tumor cells project cellular processes to ensheathe capillaries in mouse medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of β-catenin. Piezo2 knockout reverses WNT/β-catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances the MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie treatment failures in brain cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2023
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12. Pan-cancer analysis of non-coding transcripts reveals the prognostic onco-lncRNA HOXA10-AS in gliomas.
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Isaev K, Jiang L, Wu S, Lee CA, Watters V, Fort V, Tsai R, Coutinho FJ, Hussein SMI, Zhang J, Wu J, Dirks PB, Schramek D, and Reimand J
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- Animals, Biomarkers, Tumor genetics, Brain Neoplasms genetics, Brain Neoplasms pathology, Cell Line, Tumor, Cell Movement, Cell Proliferation, Databases, Genetic, Gene Expression Regulation, Neoplastic, Glioma genetics, Glioma pathology, Humans, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Machine Learning, Mice, Inbred NOD, Mice, SCID, Mutation, Neoplasm Invasiveness, Predictive Value of Tests, Prognosis, RNA, Long Noncoding genetics, Reproducibility of Results, Signal Transduction, Mice, Biomarkers, Tumor metabolism, Brain Neoplasms metabolism, Gene Expression Profiling, Glioma metabolism, RNA, Long Noncoding metabolism, Transcriptome
- Abstract
Long non-coding RNAs (lncRNAs) are increasingly recognized as functional units in cancer and powerful biomarkers; however, most remain uncharacterized. Here, we analyze 5,592 prognostic lncRNAs in 9,446 cancers of 30 types using machine learning. We identify 166 lncRNAs whose expression correlates with survival and improves the accuracy of common clinical variables, molecular features, and cancer subtypes. Prognostic lncRNAs are often characterized by switch-like expression patterns. In low-grade gliomas, HOXA10-AS activation is a robust marker of poor prognosis that complements IDH1/2 mutations, as validated in another retrospective cohort, and correlates with developmental pathways in tumor transcriptomes. Loss- and gain-of-function studies in patient-derived glioma cells, organoids, and xenograft models identify HOXA10-AS as a potent onco-lncRNA that regulates cell proliferation, contact inhibition, invasion, Hippo signaling, and mitotic and neuro-developmental pathways. Our study underscores the pan-cancer potential of the non-coding transcriptome for identifying biomarkers and regulators of cancer progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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13. The DEAD-box helicase DDX56 is a conserved stemness regulator in normal and cancer stem cells.
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Pryszlak M, Wiggans M, Chen X, Jaramillo JE, Burns SE, Richards LM, Pugh TJ, Kaplan DR, Huang X, Dirks PB, and Pearson BJ
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- Adult Stem Cells metabolism, Animals, Cell Line, Tumor, Cell Lineage, Cell Nucleolus metabolism, Cell Proliferation, Cell Self Renewal, Cell Survival, Cerebral Cortex cytology, DEAD-box RNA Helicases genetics, Drosophila metabolism, Drosophila Proteins metabolism, Gene Expression Regulation, Neoplastic, Genomics, Glioblastoma genetics, Glioblastoma pathology, HEK293 Cells, Humans, Mice, Models, Biological, Neoplastic Stem Cells pathology, Neural Stem Cells metabolism, Planarians cytology, Planarians metabolism, RNA Interference, Ribosome Subunits metabolism, Treatment Outcome, Up-Regulation genetics, DEAD-box RNA Helicases metabolism, Neoplastic Stem Cells metabolism
- Abstract
Across the animal kingdom, adult tissue homeostasis is regulated by adult stem cell activity, which is commonly dysregulated in human cancers. However, identifying key regulators of stem cells in the milieu of thousands of genes dysregulated in a given cancer is challenging. Here, using a comparative genomics approach between planarian adult stem cells and patient-derived glioblastoma stem cells (GSCs), we identify and demonstrate the role of DEAD-box helicase DDX56 in regulating aspects of stemness in four stem cell systems: planarians, mouse neural stem cells, human GSCs, and a fly model of glioblastoma. In a human GSC line, DDX56 localizes to the nucleolus, and using planarians, when DDX56 is lost, stem cells dysregulate expression of ribosomal RNAs and lose nucleolar integrity prior to stem cell death. Together, a comparative genomic approach can be used to uncover conserved stemness regulators that are functional in both normal and cancer stem cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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14. Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.
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Michealraj KA, Kumar SA, Kim LJY, Cavalli FMG, Przelicki D, Wojcik JB, Delaidelli A, Bajic A, Saulnier O, MacLeod G, Vellanki RN, Vladoiu MC, Guilhamon P, Ong W, Lee JJY, Jiang Y, Holgado BL, Rasnitsyn A, Malik AA, Tsai R, Richman CM, Juraschka K, Haapasalo J, Wang EY, De Antonellis P, Suzuki H, Farooq H, Balin P, Kharas K, Van Ommeren R, Sirbu O, Rastan A, Krumholtz SL, Ly M, Ahmadi M, Deblois G, Srikanthan D, Luu B, Loukides J, Wu X, Garzia L, Ramaswamy V, Kanshin E, Sánchez-Osuna M, El-Hamamy I, Coutinho FJ, Prinos P, Singh S, Donovan LK, Daniels C, Schramek D, Tyers M, Weiss S, Stein LD, Lupien M, Wouters BG, Garcia BA, Arrowsmith CH, Sorensen PH, Angers S, Jabado N, Dirks PB, Mack SC, Agnihotri S, Rich JN, and Taylor MD
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- Animals, Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Line, Cell Proliferation genetics, DNA Methylation genetics, Epigenomics methods, Histones genetics, Histones metabolism, Humans, Infant, Lysine genetics, Lysine metabolism, Male, Mice, Inbred C57BL, Mutation genetics, Ependymoma genetics, Ependymoma metabolism, Epigenome genetics, Infratentorial Neoplasms genetics, Infratentorial Neoplasms metabolism
- Abstract
Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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15. Roadmap for the Emerging Field of Cancer Neuroscience.
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Monje M, Borniger JC, D'Silva NJ, Deneen B, Dirks PB, Fattahi F, Frenette PS, Garzia L, Gutmann DH, Hanahan D, Hervey-Jumper SL, Hondermarck H, Hurov JB, Kepecs A, Knox SM, Lloyd AC, Magnon C, Saloman JL, Segal RA, Sloan EK, Sun X, Taylor MD, Tracey KJ, Trotman LC, Tuveson DA, Wang TC, White RA, and Winkler F
- Subjects
- Humans, Neurosciences, Neoplasms metabolism, Nervous System metabolism
- Abstract
Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of "cancer neuroscience" and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions., Competing Interests: Declaration of Interests M.M., P.S.F., T.C.W, H.H., E.K.S. and D.A.T. are on the SAB for Cygnal Therapeutics. J.B.H. is an employee of Cygnal Therapeutics. F.W. is co-founder of Divide & Conquer (DC Europa Ltd)., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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16. Medulloblastoma Arises from the Persistence of a Rare and Transient Sox2 + Granule Neuron Precursor.
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Selvadurai HJ, Luis E, Desai K, Lan X, Vladoiu MC, Whitley O, Galvin C, Vanner RJ, Lee L, Whetstone H, Kushida M, Nowakowski T, Diamandis P, Hawkins C, Bader G, Kriegstein A, Taylor MD, and Dirks PB
- Subjects
- Animals, Cell Lineage genetics, Cells, Cultured, Cerebellar Neoplasms pathology, Cerebellum embryology, Female, Hedgehog Proteins metabolism, Humans, Male, Mice, Knockout, Mice, Transgenic, Neoplasm Recurrence, Local pathology, Neural Stem Cells metabolism, Neurogenesis, Neurons metabolism, SOXB1 Transcription Factors physiology, Signal Transduction physiology, Single-Cell Analysis methods, Medulloblastoma etiology, Medulloblastoma metabolism, SOXB1 Transcription Factors metabolism
- Abstract
Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2
+ cells at the apex of tumor progression and relapse. To test whether this mechanism is rooted in a normal developmental process, we studied the role of Sox2 in cerebellar development. We find that the external germinal layer (EGL) is derived from embryonic Sox2+ precursors and that the EGL maintains a rare fraction of Sox2+ cells during the first postnatal week. Through lineage tracing and single-cell analysis, we demonstrate that these Sox2+ cells are within the Atoh1+ lineage, contribute extensively to adult granule neurons, and resemble Sox2+ tumor cells. Critically, constitutive activation of the SHH pathway leads to their aberrant persistence in the EGL and rapid tumor onset. We propose that failure to eliminate this rare but potent developmental population is the tumor initiation mechanism in SHH-subgroup MB., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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17. Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.
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Ryall S, Zapotocky M, Fukuoka K, Nobre L, Guerreiro Stucklin A, Bennett J, Siddaway R, Li C, Pajovic S, Arnoldo A, Kowalski PE, Johnson M, Sheth J, Lassaletta A, Tatevossian RG, Orisme W, Qaddoumi I, Surrey LF, Li MM, Waanders AJ, Gilheeney S, Rosenblum M, Bale T, Tsang DS, Laperriere N, Kulkarni A, Ibrahim GM, Drake J, Dirks P, Taylor MD, Rutka JT, Laughlin S, Shroff M, Shago M, Hazrati LN, D'Arcy C, Ramaswamy V, Bartels U, Huang A, Bouffet E, Karajannis MA, Santi M, Ellison DW, Tabori U, and Hawkins C
- Subjects
- Adolescent, Brain Neoplasms classification, Brain Neoplasms pathology, Child, Child, Preschool, Cohort Studies, Female, Gene Expression Profiling, Glioma classification, Glioma pathology, Humans, Infant, Infant, Newborn, Male, Mitogen-Activated Protein Kinases genetics, Neurofibromin 1 genetics, Oncogene Proteins, Fusion genetics, Proto-Oncogene Proteins B-raf genetics, ras Proteins genetics, Biomarkers, Tumor genetics, Brain Neoplasms genetics, DNA Copy Number Variations, Gene Expression Regulation, Neoplastic, Gene Rearrangement, Glioma genetics, Mutation
- Abstract
Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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18. Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma.
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Yin WC, Satkunendran T, Mo R, Morrissy S, Zhang X, Huang ES, Uusküla-Reimand L, Hou H, Son JE, Liu W, Liu YC, Zhang J, Parker J, Wang X, Farooq H, Selvadurai H, Chen X, Sau-Wai Ngan E, Cheng SY, Dirks PB, Angers S, Wilson MD, Taylor MD, and Hui CC
- Published
- 2020
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19. Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.
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Krug B, De Jay N, Harutyunyan AS, Deshmukh S, Marchione DM, Guilhamon P, Bertrand KC, Mikael LG, McConechy MK, Chen CCL, Khazaei S, Koncar RF, Agnihotri S, Faury D, Ellezam B, Weil AG, Ursini-Siegel J, De Carvalho DD, Dirks PB, Lewis PW, Salomoni P, Lupien M, Arrowsmith C, Lasko PF, Garcia BA, Kleinman CL, Jabado N, and Mack SC
- Published
- 2019
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20. Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis.
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Huang M, Tailor J, Zhen Q, Gillmor AH, Miller ML, Weishaupt H, Chen J, Zheng T, Nash EK, McHenry LK, An Z, Ye F, Takashima Y, Clarke J, Ayetey H, Cavalli FMG, Luu B, Moriarity BS, Ilkhanizadeh S, Chavez L, Yu C, Kurian KM, Magnaldo T, Sevenet N, Koch P, Pollard SM, Dirks P, Snyder MP, Largaespada DA, Cho YJ, Phillips JJ, Swartling FJ, Morrissy AS, Kool M, Pfister SM, Taylor MD, Smith A, and Weiss WA
- Subjects
- Animals, Basal Cell Nevus Syndrome metabolism, Basal Cell Nevus Syndrome pathology, Brain Neoplasms metabolism, Brain Neoplasms pathology, Carcinogenesis genetics, DEAD-box RNA Helicases genetics, Disease Models, Animal, Genetic Engineering, Genetic Predisposition to Disease, Humans, Medulloblastoma metabolism, Medulloblastoma pathology, Mice, Mice, SCID, N-Myc Proto-Oncogene Protein genetics, Neoplasm Proteins genetics, Patched-1 Receptor genetics, Stem Cell Transplantation, Transplantation, Heterologous, Basal Cell Nevus Syndrome genetics, Brain Neoplasms genetics, Medulloblastoma genetics, N-Myc Proto-Oncogene Protein metabolism, Neural Stem Cells physiology, Neuroepithelial Cells physiology, Pluripotent Stem Cells physiology
- Abstract
Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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21. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.
- Author
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Sin-Chan P, Mumal I, Suwal T, Ho B, Fan X, Singh I, Du Y, Lu M, Patel N, Torchia J, Popovski D, Fouladi M, Guilhamon P, Hansford JR, Leary S, Hoffman LM, Mulcahy Levy JM, Lassaletta A, Solano-Paez P, Rivas E, Reddy A, Gillespie GY, Gupta N, Van Meter TE, Nakamura H, Wong TT, Ra YS, Kim SK, Massimi L, Grundy RG, Fangusaro J, Johnston D, Chan J, Lafay-Cousin L, Hwang EI, Wang Y, Catchpoole D, Michaud J, Ellezam B, Ramanujachar R, Lindsay H, Taylor MD, Hawkins CE, Bouffet E, Jabado N, Singh SK, Kleinman CL, Barsyte-Lovejoy D, Li XN, Dirks PB, Lin CY, Mack SC, Rich JN, and Huang A
- Subjects
- Biomarkers, Tumor, Brain Neoplasms diagnosis, Brain Neoplasms therapy, Cell Cycle genetics, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic genetics, Chromosomes, Human, Pair 2, DNA Copy Number Variations, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Models, Biological, Neoplasms, Germ Cell and Embryonal diagnosis, Neoplasms, Germ Cell and Embryonal therapy, Oncogenes, Brain Neoplasms etiology, Chromosomes, Human, Pair 19, MicroRNAs genetics, Multigene Family, N-Myc Proto-Oncogene Protein genetics, Neoplasms, Germ Cell and Embryonal etiology, RNA-Binding Proteins genetics
- Abstract
Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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22. Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells.
- Author
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MacLeod G, Bozek DA, Rajakulendran N, Monteiro V, Ahmadi M, Steinhart Z, Kushida MM, Yu H, Coutinho FJ, Cavalli FMG, Restall I, Hao X, Hart T, Luchman HA, Weiss S, Dirks PB, and Angers S
- Subjects
- Animals, Brain Neoplasms drug therapy, Brain Neoplasms mortality, Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm genetics, Endopeptidases genetics, Endopeptidases metabolism, Endosomal Sorting Complexes Required for Transport genetics, Endosomal Sorting Complexes Required for Transport metabolism, Female, Gene Expression Regulation, Neoplastic drug effects, Gene Library, Glioblastoma drug therapy, Glioblastoma mortality, Histone Methyltransferases metabolism, Humans, Mice, Mice, SCID, Neoplastic Stem Cells drug effects, Suppressor of Cytokine Signaling 3 Protein genetics, Suppressor of Cytokine Signaling 3 Protein metabolism, Survival Analysis, Temozolomide therapeutic use, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase metabolism, Brain Neoplasms pathology, CRISPR-Cas Systems genetics, Gene Editing methods, Glioblastoma pathology, Neoplastic Stem Cells metabolism, Temozolomide pharmacology
- Abstract
Glioblastoma therapies have remained elusive due to limitations in understanding mechanisms of growth and survival of the tumorigenic population. Using CRISPR-Cas9 approaches in patient-derived GBM stem cells (GSCs) to interrogate function of the coding genome, we identify actionable pathways responsible for growth, which reveal the gene-essential circuitry of GBM stemness and proliferation. In particular, we characterize members of the SOX transcription factor family, SOCS3, USP8, and DOT1L, and protein ufmylation as important for GSC growth. Additionally, we reveal mechanisms of temozolomide resistance that could lead to combination strategies. By reaching beyond static genome analysis of bulk tumors, with a genome-wide functional approach, we reveal genetic dependencies within a broad range of biological processes to provide increased understanding of GBM growth and treatment resistance., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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23. Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma.
- Author
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Yin WC, Satkunendran T, Mo R, Morrissy S, Zhang X, Huang ES, Uusküla-Reimand L, Hou H, Son JE, Liu W, Liu YC, Zhang J, Parker J, Wang X, Farooq H, Selvadurai H, Chen X, Ngan ES, Cheng SY, Dirks PB, Angers S, Wilson MD, Taylor MD, and Hui CC
- Subjects
- Animals, Hedgehog Proteins genetics, Humans, Medulloblastoma genetics, Mice, Cell Transformation, Neoplastic genetics, Nuclear Proteins genetics, Repressor Proteins genetics, Zinc Finger Protein Gli2 genetics
- Abstract
SUFU alterations are common in human Sonic Hedgehog (SHH) subgroup medulloblastoma (MB). However, its tumorigenic mechanisms have remained elusive. Here, we report that loss of Sufu alone is unable to induce MB formation in mice, due to insufficient Gli2 activation. Simultaneous loss of Spop, an E3 ubiquitin ligase targeting Gli2, restores robust Gli2 activation and induces rapid MB formation in Sufu knockout background. We also demonstrated a tumor-promoting role of Sufu in Smo-activated MB (∼60% of human SHH MB) by maintaining robust Gli activity. Having established Gli2 activation as a key driver of SHH MB, we report a comprehensive analysis of its targetome. Furthermore, we identified Atoh1 as a target and molecular accomplice of Gli2 that activates core SHH MB signature genes in a synergistic manner. Overall, our work establishes the dual role of SUFU in SHH MB and provides mechanistic insights into transcriptional regulation underlying Gli2-mediated SHH MB tumorigenesis., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
24. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.
- Author
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Garzia L, Kijima N, Morrissy AS, De Antonellis P, Guerreiro-Stucklin A, Holgado BL, Wu X, Wang X, Parsons M, Zayne K, Manno A, Kuzan-Fischer C, Nor C, Donovan LK, Liu J, Qin L, Garancher A, Liu KW, Mansouri S, Luu B, Thompson YY, Ramaswamy V, Peacock J, Farooq H, Skowron P, Shih DJH, Li A, Ensan S, Robbins CS, Cybulsky M, Mitra S, Ma Y, Moore R, Mungall A, Cho YJ, Weiss WA, Chan JA, Hawkins CE, Massimino M, Jabado N, Zapotocky M, Sumerauer D, Bouffet E, Dirks P, Tabori U, Sorensen PHB, Brastianos PK, Aldape K, Jones SJM, Marra MA, Woodgett JR, Wechsler-Reya RJ, Fults DW, and Taylor MD
- Published
- 2018
- Full Text
- View/download PDF
25. Comprehensive Analysis of Hypermutation in Human Cancer.
- Author
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Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, and Shlien A
- Subjects
- Adult, Child, Cluster Analysis, DNA Polymerase II genetics, DNA Polymerase III genetics, DNA Replication, Humans, Mutation, Neoplasms classification, Neoplasms pathology, Neoplasms therapy, Poly-ADP-Ribose Binding Proteins genetics, Neoplasms genetics
- Abstract
We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
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26. ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells.
- Author
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Park NI, Guilhamon P, Desai K, McAdam RF, Langille E, O'Connor M, Lan X, Whetstone H, Coutinho FJ, Vanner RJ, Ling E, Prinos P, Lee L, Selvadurai H, Atwal G, Kushida M, Clarke ID, Voisin V, Cusimano MD, Bernstein M, Das S, Bader G, Arrowsmith CH, Angers S, Huang X, Lupien M, and Dirks PB
- Published
- 2017
- Full Text
- View/download PDF
27. Intertumoral Heterogeneity within Medulloblastoma Subgroups.
- Author
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Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C, Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ, Ra YS, Kumabe T, López-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpeña-Diazconti M, Chico Ponce de León F, Robinson S, Zapotocky M, Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB, Rutka JT, Bader GD, Reimand J, Goldenberg A, Ramaswamy V, and Taylor MD
- Subjects
- Cluster Analysis, Cohort Studies, DNA Copy Number Variations, DNA Methylation, Gene Expression Profiling, Genomics, Humans, Medulloblastoma genetics, Medulloblastoma therapy, Medulloblastoma classification, Precision Medicine
- Abstract
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
28. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.
- Author
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Torchia J, Golbourn B, Feng S, Ho KC, Sin-Chan P, Vasiljevic A, Norman JD, Guilhamon P, Garzia L, Agamez NR, Lu M, Chan TS, Picard D, de Antonellis P, Khuong-Quang DA, Planello AC, Zeller C, Barsyte-Lovejoy D, Lafay-Cousin L, Letourneau L, Bourgey M, Yu M, Gendoo DMA, Dzamba M, Barszczyk M, Medina T, Riemenschneider AN, Morrissy AS, Ra YS, Ramaswamy V, Remke M, Dunham CP, Yip S, Ng HK, Lu JQ, Mehta V, Albrecht S, Pimentel J, Chan JA, Somers GR, Faria CC, Roque L, Fouladi M, Hoffman LM, Moore AS, Wang Y, Choi SA, Hansford JR, Catchpoole D, Birks DK, Foreman NK, Strother D, Klekner A, Bognár L, Garami M, Hauser P, Hortobágyi T, Wilson B, Hukin J, Carret AS, Van Meter TE, Hwang EI, Gajjar A, Chiou SH, Nakamura H, Toledano H, Fried I, Fults D, Wataya T, Fryer C, Eisenstat DD, Scheinemann K, Fleming AJ, Johnston DL, Michaud J, Zelcer S, Hammond R, Afzal S, Ramsay DA, Sirachainan N, Hongeng S, Larbcharoensub N, Grundy RG, Lulla RR, Fangusaro JR, Druker H, Bartels U, Grant R, Malkin D, McGlade CJ, Nicolaides T, Tihan T, Phillips J, Majewski J, Montpetit A, Bourque G, Bader GD, Reddy AT, Gillespie GY, Warmuth-Metz M, Rutkowski S, Tabori U, Lupien M, Brudno M, Schüller U, Pietsch T, Judkins AR, Hawkins CE, Bouffet E, Kim SK, Dirks PB, Taylor MD, Erdreich-Epstein A, Arrowsmith CH, De Carvalho DD, Rutka JT, Jabado N, and Huang A
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Central Nervous System Neoplasms drug therapy, DNA Methylation, Dasatinib pharmacology, Dasatinib therapeutic use, Epigenesis, Genetic drug effects, Humans, Mutation, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Pyrimidines pharmacology, Pyrimidines therapeutic use, Receptor, Platelet-Derived Growth Factor beta antagonists & inhibitors, Rhabdoid Tumor drug therapy, Teratoma drug therapy, Central Nervous System Neoplasms genetics, Chromatin genetics, Epigenomics methods, Receptor, Platelet-Derived Growth Factor beta genetics, Rhabdoid Tumor genetics, SMARCB1 Protein genetics, Teratoma genetics
- Abstract
We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
29. Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells.
- Author
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Dolma S, Selvadurai HJ, Lan X, Lee L, Kushida M, Voisin V, Whetstone H, So M, Aviv T, Park N, Zhu X, Xu C, Head R, Rowland KJ, Bernstein M, Clarke ID, Bader G, Harrington L, Brumell JH, Tyers M, and Dirks PB
- Subjects
- Animals, Autophagy, Brain Neoplasms metabolism, Cell Differentiation drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Gene Expression Regulation, Neoplastic drug effects, Glioblastoma metabolism, Humans, Mice, Neoplastic Stem Cells cytology, Neoplastic Stem Cells drug effects, Neural Stem Cells cytology, Neural Stem Cells pathology, Receptors, Dopamine D4 antagonists & inhibitors, Signal Transduction drug effects, Small Molecule Libraries pharmacology, Survival Analysis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Neural Stem Cells drug effects, Receptors, Dopamine D4 metabolism, Small Molecule Libraries administration & dosage
- Abstract
Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G0/G1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
30. MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.
- Author
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Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, Remke M, Li R, Takayama N, Desai K, Lee L, Lan X, Park NI, Barsyte-Lovejoy D, Smil D, Sturm D, Kushida MM, Head R, Cusimano MD, Bernstein M, Clarke ID, Dick JE, Pfister SM, Rich JN, Arrowsmith CH, Taylor MD, Jabado N, Bazett-Jones DP, Lupien M, and Dirks PB
- Subjects
- Adolescent, Adult, Animals, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms mortality, Brain Neoplasms pathology, Cell Differentiation, Cell Proliferation, Child, Child, Preschool, DNA Methylation, DNA-Binding Proteins genetics, Drug Design, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma mortality, Glioblastoma pathology, Histones genetics, Humans, Kaplan-Meier Estimate, Mice, Inbred NOD, Mice, SCID, Molecular Targeted Therapy, Mutation, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Prognosis, RNA Interference, Signal Transduction, Time Factors, Transfection, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Young Adult, Brain Neoplasms metabolism, Cell Self Renewal drug effects, Chromatin Assembly and Disassembly drug effects, DNA-Binding Proteins metabolism, Glioblastoma metabolism, Histones metabolism, Neoplastic Stem Cells metabolism
- Abstract
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
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31. Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma.
- Author
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Vanner RJ, Remke M, Gallo M, Selvadurai HJ, Coutinho F, Lee L, Kushida M, Head R, Morrissy S, Zhu X, Aviv T, Voisin V, Clarke ID, Li Y, Mungall AJ, Moore RA, Ma Y, Jones SJ, Marra MA, Malkin D, Northcott PA, Kool M, Pfister SM, Bader G, Hochedlinger K, Korshunov A, Taylor MD, and Dirks PB
- Subjects
- Animals, Antigens, Nuclear metabolism, Antineoplastic Agents pharmacology, Biomarkers, Tumor genetics, Cell Lineage, Cerebellar Neoplasms drug therapy, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, DNA-Binding Proteins, Dose-Response Relationship, Drug, Doublecortin Domain Proteins, Drug Resistance, Neoplasm, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Hedgehog Proteins genetics, Medulloblastoma drug therapy, Medulloblastoma genetics, Mice, Mice, Transgenic, Microtubule-Associated Proteins metabolism, Molecular Sequence Data, Neoplasm Recurrence, Local, Nerve Tissue Proteins metabolism, Neurogenesis, Neuropeptides metabolism, Nuclear Proteins metabolism, Patched Receptors, Plicamycin pharmacology, Prognosis, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Receptors, G-Protein-Coupled metabolism, SOXB1 Transcription Factors genetics, Smoothened Receptor, Time Factors, Tumor Cells, Cultured, Biomarkers, Tumor metabolism, Cell Proliferation drug effects, Cerebellar Neoplasms metabolism, Hedgehog Proteins metabolism, Medulloblastoma metabolism, SOXB1 Transcription Factors metabolism
- Abstract
Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox2(+) cells propagate sonic hedgehog subgroup medulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox2(+) cells produce rapidly cycling doublecortin(+) progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox2(+) cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox2(+) cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox2(+) cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox2(+) cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
32. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors.
- Author
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Li M, Lee KF, Lu Y, Clarke I, Shih D, Eberhart C, Collins VP, Van Meter T, Picard D, Zhou L, Boutros PC, Modena P, Liang ML, Scherer SW, Bouffet E, Rutka JT, Pomeroy SL, Lau CC, Taylor MD, Gajjar A, Dirks PB, Hawkins CE, and Huang A
- Subjects
- Animals, Brain Neoplasms pathology, Cell Differentiation, Humans, Mice, Neuroectodermal Tumors, Primitive pathology, Signal Transduction, Stem Cells, Wnt Proteins metabolism, Brain Neoplasms genetics, Chromosomes, Human, Pair 19, Gene Amplification, MicroRNAs genetics, Neuroectodermal Tumors, Primitive genetics
- Abstract
We discovered a high-level amplicon involving the chr19q13.41 microRNA (miRNA) cluster (C19MC) in 11/45 ( approximately 25%) primary CNS-PNET, which results in striking overexpression of miR-517c and 520g. Constitutive expression of miR-517c or 520g promotes in vitro and in vivo oncogenicity, modulates cell survival, and robustly enhances growth of untransformed human neural stem cells (hNSCs) in part by upregulating WNT pathway signaling and restricting differentiation of hNSCs. Remarkably, the C19MC amplicon, which is very rare in other brain tumors (1/263), identifies an aggressive subgroup of CNS-PNET with distinct gene-expression profiles, characteristic histology, and dismal survival. Our data implicate miR-517c and 520g as oncogenes and promising biological markers for CNS-PNET and provide important insights into oncogenic properties of the C19MC locus.
- Published
- 2009
- Full Text
- View/download PDF
33. Bmi1 and cell of origin determinants of brain tumor phenotype.
- Author
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Dirks P
- Subjects
- Animals, Astrocytes pathology, Brain Neoplasms genetics, Brain Neoplasms pathology, Cell Differentiation, Cell Proliferation, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Cyclin-Dependent Kinase Inhibitor p16 deficiency, Cyclin-Dependent Kinase Inhibitor p16 genetics, ErbB Receptors genetics, ErbB Receptors metabolism, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma pathology, Humans, Mice, Mice, Knockout, Mutation, Neoplasm Staging, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Neurons pathology, Nuclear Proteins deficiency, Nuclear Proteins genetics, Phenotype, Polycomb Repressive Complex 1, Proto-Oncogene Proteins deficiency, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Stem Cells pathology, Time Factors, Astrocytes metabolism, Brain Neoplasms metabolism, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Glioblastoma metabolism, Neurons metabolism, Nuclear Proteins metabolism, Proto-Oncogene Proteins metabolism, Repressor Proteins metabolism, Signal Transduction genetics, Stem Cells metabolism
- Abstract
Glioblastomas frequently express oncogenic EGFR and loss of the Ink4a/Arf locus. Bmi1, a positive regulator of stem cell self renewal, may be critical to drive brain tumor growth. In this issue of Cancer Cell, Bruggeman and colleagues suggest that brain tumors with these molecular alterations can be initiated in both neural precursor and differentiated cell compartments in the absence of Bmi1; however, tumorigenicity is reduced, and tumors contain fewer precursor cells. Surprisingly, tumors appear less malignant when initiated in precursor cells. Bmi1-deficient tumors also had fewer neuronal lineage cells, suggesting a role for Bmi1 in determination of cell lineage and tumor phenotype.
- Published
- 2007
- Full Text
- View/download PDF
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