Weiss, SamuelCairncross, J. GregoryChesnelong, Charles2017-01-102017-01-1020172017Chesnelong, 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/26994http://hdl.handle.net/11023/3554Gliomas 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.engUniversity 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.Biology--CellBiology--MolecularNeuroscienceBiophysics--MedicalOncologyGlioblastomaBrain TumorsIDH1/2 mutationSTAT3Epithelial to Mesenchymal Transition (EMT)Brain Tumor Initiating Cells (BTICs)GliomasSLUGSNAI2Cancerprecursor stateCancer Stem CellMolecular Pathways to Initiation and Progression in Gliomasdoctoral thesis10.11575/PRISM/26994