Browsing by Author "Weiss, Samuel"
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- ItemOpen AccessA Novel Combinatorial Strategy Targeting the EGFR and JAK2/STAT3 Pathways in GBM Brain Tumour Initiating Cells(2017) Jensen, Katharine; Weiss, Samuel; Luchman, H. Artee; Grewal, Savraj; Mahoney, Douglas; Narendran, AruGlioblastoma multiforme (GBM) is the most prevalent and aggressive primary adult brain tumour with a median survival of only 15 months. Despite aggressive treatment, long-lasting tumour control cannot be achieved and disease recurrence is inevitable. Brain tumour initiating cells (BTICs) are postulated to be at the root of disease initiation and recurrence, suggesting that BTIC targeting therapies are crucial to establishing tumour control. Resistance of cancer cells to targeted therapies can occur through the activation of compensating signalling pathways. Using a BTIC model of GBM, we identified the activation of signal transducer and activator of transcription (STAT)3 as a compensation mechanism in response to epidermal growth factor receptor (EGFR) inhibition. We showed that concurrent inhibition of EGFR and STAT3 was highly effective in vitro, as it dramatically decreased BTIC viability and neurosphere formation. Combined inhibition of EGFR and STAT3 resulted in the attenuation of both oncogenic signalling pathways. In vivo, systemic administration of the EGFR inhibitor, afatinib, and the JAK2 inhibitor, pacritinib, demonstrated favourable pharmacokinetic and pharmacodynamic properties, displaying blood-brain barrier penetration and on-target activity in orthotopic BTIC xenografts. Overall, these data provide a promising strategy to overcome EGFR inhibitor resistance by targeting two oncogenic pathways in combination.
- ItemOpen AccessA role for adult mammalian central nervious system neurogenesis in social behaviours(2009) Mak, Gloria K.; Weiss, Samuel
- ItemOpen AccessCell genesis in the mammalian central nervous system(2006) Gregg, Christopher T.; Weiss, Samuel
- ItemOpen AccessCellular and molecular properties of mammalian ventral forebrain precursors(2003) Chojnacki, Andrew K.; Weiss, Samuel
- ItemOpen AccessCharacterization of the striatal metabotropic glutamate receptor in vitro(1992) Symons, Bruce P.; Weiss, Samuel
- ItemOpen AccessCulture and characterization of human brain tumor stem cells(2011) Kelly, John James Patrick; Weiss, SamuelDiffusely infiltrating gliomas, of which glioblastoma (GBM) is most common, are highly aggressive brain tumors with dismal outcomes. Application of the Cancer Stem Cell (CSC) hypothesis to glioma led to the discovery of Brain Tumor Stem Cells (BTSCs) and a direct link to Neural Stem Cells (NSCs). In this thesis I begin by trying to identify characteristics that distinguish BTSCs from NSCs. I cultured cells isolated from GBMs, using the neurosphere culture system, in order to understand their growth requirements. GBM BTSCs proliferated in the absence of exogenous mitogenic stimulation and gave rise to multipotent GBM spheres that were capable of self-renewal. Epidermal growth factor and fibroblast growth factor-2 enhanced GBM BTSC survival and proliferation. Implantation of exogenous mitogen independent GBM BTSCs led to the formation of highly invasive intracranial tumors in immunocompromised mice. Thus, exogenous mitogen independence is one characteristic that distinguishes GBM BTSCs from NSCs. I then ask whether BTSCs can be isolated from other gliomas, specifically oligodendroglioma. Investigating the biology of oligodendroglioma, and its characteristic combined deletion of chromosomal arms 1 p and 19q, has been hampered by the lack of cell lines that harbor these traits. Cells from anaplastic oligodendrogliomas cultured in serum-free conditions, followed by serial propagation and expansion, led to the establishment of permanent cell lines that maintained the genetic signature of the parent tumors. Furthermore, these oligodendroglioma cells displayed features of BTSCs in vitro. These lines may be important tools for understanding the biology of oligodendroglioma and the function of their defining genetic traits. Finally, I employed the neurosphere culture system in order to generate 70 cell lines that collectively comprise a cellular model system of GBM. This robust model system harbors characteristic genetic abnormalities of GBM that permit sub-grouping of the cell lines. Importantly, this system recapitulates the heterogeneity of GBM and facilitates both in vitro and in vivo studies of phenotypic and molecular sub-groups. By coupling cell line generation with molecular characteristics and patient outcome, the model system has direct clinical relevance. In sum, the results demonstrate that glioma heterogeneity is evident in BTSCs isolated from individual tumors. This unique experimental system will permit elucidation of mechanisms that underlie glioma BTSC biology together with preclinical studies that evaluate novel therapeutic strategies.
- ItemOpen AccessGamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor(Public Library of Science, 2008-11-25) Wang, LiMei; Rahn, Jennifer J.; Lun, XueQing; Sun, Beichen; Kelly, John J. P.; Weiss, Samuel; Robbins, Stephen M.; Forsyth, Peter A.; Senger, Donna L.
- ItemOpen AccessGranulocyte macrophage-colony stimulating factor actions on the neural stem cell to oligodendrocyte lineage(2005) Dubois, Tina; Weiss, Samuel
- ItemUnknownGrowth factor stimulated functional improvement following cortical ischemia(2010) Chalmers, Trudi E.; Weiss, Samuel
- ItemOpen AccessIdentification and characterization of stem cells in the adult mouse spinal cord(1997) Dunne, Christine E.; Weiss, Samuel
- ItemOpen AccessInterrogating the Epigenetic Determinants of State Heterogeneity in Adult Glioblastoma(2023-01-24) Nikolic, Ana; Gallo, Marco; Chan, Jennifer; Weiss, Samuel; Goodarzi, Aaron; Hawkins, CynthiaGlioblastoma is the most common malignant brain tumour in adults, and prognosis remains poor, with most patients dying in a year or two despite aggressive treatment. These tumours have high degrees of intratumoral heterogeneity, with a subpopulation of cells having stem cell properties. The drivers of this stem cell phenotype are complex, and include a large number of epigenetic and genetic factors. In this thesis, I explore glioblastoma heterogeneity in two distinct ways: I use single-cell chromatin accessibility data to explore influences of copy number alterations on the glioblastoma epigenome, and I apply functional experimental techniques and genomics to characterize macroH2A2, an epigenetic regulator in this disease. In the first part of my thesis, I develop a tool for calling copy number alterations in single-cell ATAC-seq data, called CopyscAT, and show that glioblastoma tumours have limited intratumoral genetic heterogeneity. In addition, genetic subclones share similar epigenetic profiles, but with slightly different predispositions to acquiring distinct cellular states. In the second section of the thesis, I focus on the role of macroH2A2, a histone variant involved in development and cancer. I find that expression of macroH2A2 is associated with improved prognosis in glioblastoma patients, especially in patients receiving treatment. Examining existing datasets, I find that macroH2A2 expression is enriched in neural progenitor-like cells and repressed at the leading edge of tumours, and confirm this in primary patient specimens. MacroH2A2 is associated with reduced self-renewal in vitro and in vivo and knockdown of the protein increases self-renewal markers, reduces the proportion of CD44-positive cells, and shortens mouse survival. Genome-wide, macroH2A2 knockdown results in altered accessibility, with loss of early response (FOS/AP-1) motifs, which I confirm in patient-derived single-cell ATAC-seq data. Chromatin immunoprecipitation confirms that direct effects of macroH2A2 are largely repressive in nature. Lastly, a screen of epigenetic drugs identifies a compound, MI-3, capable of increasing macroH2A2 levels, and shows that macroH2A2 repression impairs sensitivity to this compound. This work contributes novel ideas to the regulation of cell states and fates in glioblastoma.
- ItemOpen AccessInvestigating the Role of the Mediator Complex in Brain Tumour Stem Cells(2021-07-27) Cutts, Emilie; Weiss, Samuel; Luchman, H. Artee; Goodarzi, Aaron; Grewal, SavrajThe regulation of gene transcription is highly controlled and frequently modified in cancer cells. Glioblastoma (GBM) is a fast-growing, malignant grade IV astrocytoma, with a median patient survival of approximately 15 months. Transcriptional dysregulation contributes to the malignant phenotypes of brain tumour stem cells (BTSCs), which are thought to promote GBM initiation and progression. In response to dynamic tumour microenvironment signals, BTSC plasticity has been shown to facilitate adaptive transcriptional programs to enable cellular proliferation and survival. Therefore, there is a growing interest in elucidating the precise mechanisms of transcriptional regulation which promote BTSC plasticity. The Mediator complex acts as a functional bridge between enhancer-bound transcription factors and the basal transcription machinery at core promoters to activate or repress gene transcription. Regulatory transcription factors, involved in cellular response to environmental cues, have been shown to interact with the Mediator tail module. Therefore, the Mediator complex is thought to integrate environmental signals to facilitate context-dependent gene expression. Recently, we identified a role for the Mediator tail module linked to an epigenetic mechanism of gene regulation important for BTSC growth and differentiation, driven by the histone methyltransferase DOT1L. However, the precise contributions of individual tail subunits for transcriptional regulation in BTSCs warrant further investigation. To determine the extent of context-dependent gene transcription regulated by the Mediator complex tail module, I generated single gene knockouts to individually target all 7 tail subunits in BTSCs. Genetic loss of any of the tail subunits had no effect on the viability, proliferation, or self-renewal potential of BTSCs grown in ideal neural stem cell culture conditions. However, orthotopic xenografts of each Mediator tail subunit knockout cell line in SCID mice, a context which more closely recapitulates the GBM tumour microenvironment, resulted in reduced tumour burden and significantly longer overall mouse survival. I further demonstrate that the Mediator tail module regulates transcriptional pathways related to neurogenesis and inflammation. In support of these findings, I identified a role for the Mediator tail module in facilitating cellular response to inflammatory cues, through the regulation of inducible nitric oxide synthase (iNOS) activity. In this study, I describe novel findings to the field of GBM by demonstrating a requirement for the Mediator complex tail module for gliomagenesis. Furthermore, I identify the Mediator complex as an important molecular player in the dynamic interplay between the GBM tumour microenvironment and BTSC gene transcription.
- ItemOpen AccessInvestigation of mitotically-active cells in the adult mouse hippocampus(1996) Rietze, Rodney; Weiss, Samuel
- ItemOpen AccessIsolation and characterization of a mammalian central nervous system stem cell(1994) Reynolds, Brent A.; Weiss, Samuel
- ItemUnknownMolecular Pathways to Initiation and Progression in Gliomas(2017) Chesnelong, Charles; Weiss, Samuel; Cairncross, J. Gregory; Schuurmans, Carol; Chan, Jennifer; Gallo, MarcoGliomas 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.
- ItemOpen AccessMolecular therapeutics for glioblastoma brain tumor stem cells(2011) Stechishin, Owen D. M.; Weiss, Samuel
- ItemOpen AccessNovel Drug Discovery for Glioblastoma Multiforme Using Brain Tumour Initiating Cells(2013-07-10) Nguyen, Stephanie; Weiss, Samuel; Luchman, ArteeGlioblastoma (GBM) is the most common and aggressive adult primary brain tumour. Populations of cells with tumour initiating capacity, termed brain tumour initiating cells (BTICs), are thought to underlie the formation, growth and recurrence of GBM. As such, therapies that target this compartment may improve the otherwise poor prognosis of this disease. Here, we identified R333, a compound targeting the JAK/STAT3 pathway, as a potent inhibitor of BTIC tumourigenicity. In vitro, R333 dramatically decreased the viability and clonogenic potential of diverse BTIC lines. In vivo, systemic treatment with R348, the prodrug form of R333, was well tolerated and demonstrated favourable pharmacokinetic properties. R348 treatment was also found to lead to a significant increase in overall median survival in an orthotopic BTIC xenograft model. Altogether, these data strongly support further investigation of this compound and potentially represent the first step toward an effective molecularly targeted therapeutic for GBM.
- ItemOpen AccessRetinoic acid enhances neuronal proliferation and astroglial differentiation in cultures of CNS stem cell-derived precursors(1998) Wohl, Cherly Ann; Weiss, Samuel
- ItemOpen AccessRoles for neural stem cells in adult mammalian olfactory behaviour(2003) Enwere, Emeka K.; Weiss, Samuel
- ItemOpen AccessThe actions of bone morphogenetic protein 2 on mammalian central nervous system stem cells and stem cell progeny(1996) Bjornson, Christopher R. R.; Weiss, Samuel