{"id":20,"date":"2017-09-15T16:03:00","date_gmt":"2017-09-15T16:03:00","guid":{"rendered":"https:\/\/wordpress-dev.med.unc.edu\/millerlab\/?page_id=20"},"modified":"2018-08-18T11:28:21","modified_gmt":"2018-08-18T15:28:21","slug":"cellular-and-epigenetic-biology-of-glioma-stem-cells","status":"publish","type":"page","link":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/research\/cellular-and-epigenetic-biology-of-glioma-stem-cells\/","title":{"rendered":"Cellular and epigenetic biology of glioma stem cells"},"content":{"rendered":"
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Glioma stem cells (GSCs) from human glioblastoma (GBM) are resistant to radiation and chemotherapy and may drive disease recurrence after therapy. Understanding the genesis of GSCs will be critical to the design of novel therapeutic approaches to manage GBM.<\/em><\/p>\n<\/header>\n

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Project summary<\/h2>\n

We\u00a0investigate the molecular mechanisms of GSC development\u00a0using\u00a0genetically-engineered mouse<\/a>\u00a0(GEM) models and\u00a0human\u00a0patient-derived xenografts<\/a>\u00a0(PDX).<\/p>\n

In particular, we focus on the molecular mechanisms by which\u00a0astrocytes<\/a>, the most abundant glial cell type in the mammalian brain, de-differentiate into GSC after acquiring oncogenic\u00a0mutations in\u00a0core glioblastoma signaling pathways<\/a>.<\/p>\n

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Brennan et al. \u00a0Cancer Cell 155(2):462 2013<\/a>.<\/p>\n

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Mechanistic studies use GEM and PDX culture systems to:<\/p>\n

Examine how core pathway mutations induce GSC-specific alterations in the epigenetic landscape of astrocytes<\/h3>\n

Integrated genomics analyses are critical for this work. \u00a0These include\u00a0FAIRE<\/a>– and\u00a0ATAC<\/a>-seq,\u00a0ChIP<\/a>-seq, and\u00a0RNA<\/a>-seq to examine mutation-induced changes in\u00a0chromatin accessibility, promoter landscapes, and transcriptomes.<\/p>\n

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Schmid et al. \u00a0Neuro-oncology 18(7):962 2016<\/a>.<\/p>\n

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Define the\u00a0transcription factors\u00a0that mediate oncogenic mutation-induced astrocyte de-differentiation into GSC<\/h3>\n

Cell culture techniques used in developmental neurobiology are critical for this work. \u00a0These include analysis of self-renewal using\u00a0neurosphere culture<\/a>,\u00a0extreme-limiting dilution<\/a>, and\u00a0multi-lineage differentiation assays.<\/p>\n

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Schmid et al. \u00a0Neuro-oncology 18(7):962 2016<\/a>.<\/p>\n

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References<\/h2>\n
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  1. Schmid RS, Simon JM,\u00a0Vitucci M,\u00a0McNeill RS,\u00a0Bash RE,\u00a0Werneke AM,\u00a0Huey L,\u00a0White KK, Ewend MG,\u00a0Wu J,\u00a0Miller CR.\u00a0 Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation, but resistant to temozolomide.\u00a0 Neuro-oncology.\u00a0 18(7):962-973 Jul 2016.\u00a0 PMID:\u00a026826202<\/a>\u00a0 PMCID:\u00a0PMC4896545<\/a><\/li>\n
  2. McNeill RS,\u00a0Vitucci M,\u00a0Wu J,\u00a0Miller CR.\u00a0 Contemporary murine models in preclinical astrocytoma drug development.\u00a0 Neuro-oncology.\u00a0 17(1):12-28 Jan 2015.\u00a0 PMID:\u00a025246428<\/a>\u00a0 PMCID:\u00a0PMC4483055<\/a><\/li>\n
  3. McNeill RS,\u00a0Schmid RS,\u00a0Bash RE,\u00a0Vitucci M,\u00a0White KK,\u00a0Werneke AM,\u00a0Constance BH,\u00a0Huff B,\u00a0Miller CR.\u00a0 Modeling astrocytoma pathogenesis in vitro and in vivo using cortical astrocytes or neural stem cells from conditional, genetically engineered mice.\u00a0 Journal of Visualized Experiments.\u00a0 90:e51763 Aug 2014.\u00a0 PMID:\u00a025146643<\/a><\/li>\n
  4. Vitucci M, Karpinich NO,\u00a0Bash RE,\u00a0Werneke AM,\u00a0Schmid RS,\u00a0White KK,\u00a0McNeill RS,\u00a0Huff B, Wang S, Van Dyke T,\u00a0Miller CR.\u00a0 Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis. \u00a0Neuro-oncology.\u00a0 15(10):1317-1329 Oct 2013.\u00a0 PMID:\u00a023814263<\/a>\u00a0 PMCID:\u00a0PMC3779038<\/a><\/li>\n<\/ol>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

    Glioma stem cells (GSCs) from human glioblastoma (GBM) are resistant to radiation and chemotherapy and may drive disease recurrence after therapy. Understanding the genesis of GSCs will be critical to the design of novel therapeutic approaches to manage GBM. Project summary We\u00a0investigate the molecular mechanisms of GSC development\u00a0using\u00a0genetically-engineered mouse\u00a0(GEM) models and\u00a0human\u00a0patient-derived xenografts\u00a0(PDX). In particular, we … Read more<\/a><\/p>\n","protected":false},"author":68816,"featured_media":0,"parent":10,"menu_order":2,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":"","_links_to":"","_links_to_target":""},"class_list":["post-20","page","type-page","status-publish","hentry","odd"],"acf":[],"_links_to":[],"_links_to_target":[],"_links":{"self":[{"href":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/wp-json\/wp\/v2\/pages\/20","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/wp-json\/wp\/v2\/users\/68816"}],"replies":[{"embeddable":true,"href":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/wp-json\/wp\/v2\/comments?post=20"}],"version-history":[{"count":0,"href":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/wp-json\/wp\/v2\/pages\/20\/revisions"}],"up":[{"embeddable":true,"href":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/wp-json\/wp\/v2\/pages\/10"}],"wp:attachment":[{"href":"https:\/\/www.med.unc.edu\/pathology\/millerlab\/wp-json\/wp\/v2\/media?parent=20"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}