Molecular Pathways to Initiation and Progression in Gliomas

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atmire.migration.oldid5248
dc.contributor.advisorWeiss, Samuel
dc.contributor.advisorCairncross, J. Gregory
dc.contributor.authorChesnelong, Charles
dc.contributor.committeememberSchuurmans, Carol
dc.contributor.committeememberChan, Jennifer
dc.contributor.committeememberGallo, Marco
dc.date.accessioned2017-01-10T22:16:20Z
dc.date.available2017-01-10T22:16:20Z
dc.date.issued2017
dc.date.submitted2017en
dc.description.abstractGliomas are the most common primary adult brain tumors. Despite current treatment, including surgery radio- and chemotherapy, these tumors continue to progress and recur with a more aggressive and resistant phenotype. Recurrence is believed to be, in no small part, due to the presence within the tumors of Brain Tumor Initiating Cells (BTICs). These cells have stem-like properties, are resistant to therapeutic effort and demonstrate enhanced tumorigenic potential. The key molecular alterations sustaining growth and therapeutic resistance in gliomas are now well described. However, targeted therapies have so far failed to make significant impact in the clinic, perhaps due to the heterogeneity and rapid evolution characteristic of these tumors. A better understanding of the players driving recurrence and the molecular pathways to initiation and progression in gliomas is hence essential to developing novel therapeutic strategies and improve clinical outcome. Isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation is found in grade II-III astrocytomas, oligodendrogliomas and in secondary glioblastomas (GBMs), but is completely absent from primary GBMs, thus reflecting a different origin and evolution. In the first section of this thesis, we study the IDH1/2 mutation in glioma and its contradictory roles during tumor initiation and progression. More specifically, we show that the IDH1/2 mutation is directly involved in downregulating glycolytic genes such as LDHA. We also report the selection of large chr2 deletions resulting in the loss of either the IDH1 wild-type or mutant allele. Although essential during initiation, we argue that the IDH1/2 mutation may be a limiting factor of tumor progression at later stages of tumorigenesis. Often considered a different disease, primary GBMs are the most aggressive and lethal primary brain tumors. In the second section of this thesis, we focus on these tumors through the study of primary GBM-derived BTICs. We report the existence of distinct precursor states (stem-like and progenitor-like) in BTICs predictive of survival and associated with GBM subtypes. Further, we highlight a STAT3-driven EMT-like process in progenitor-like BTICs, which may drive the progression towards more aggressive and resistant recurrent GBM.en_US
dc.identifier.citationChesnelong, C. (2017). Molecular Pathways to Initiation and Progression in Gliomas (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26994en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/26994
dc.identifier.urihttp://hdl.handle.net/11023/3554
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology--Cell
dc.subjectBiology--Molecular
dc.subjectNeuroscience
dc.subjectBiophysics--Medical
dc.subjectOncology
dc.subject.otherGlioblastoma
dc.subject.otherBrain Tumors
dc.subject.otherIDH1/2 mutation
dc.subject.otherSTAT3
dc.subject.otherEpithelial to Mesenchymal Transition (EMT)
dc.subject.otherBrain Tumor Initiating Cells (BTICs)
dc.subject.otherGliomas
dc.subject.otherSLUG
dc.subject.otherSNAI2
dc.subject.otherCancer
dc.subject.otherprecursor state
dc.subject.otherCancer Stem Cell
dc.titleMolecular Pathways to Initiation and Progression in Gliomas
dc.typedoctoral thesis
thesis.degree.disciplineMedical Science
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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