| SAMUEL WEISS Professor |
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My laboratory discovered a mammalian central nervous system (CNS) stem cell that can be induced to divide in cell culture and in the intact brain, and produce the three major cell types of the CNS - neurons, astrocytes and oligodendrocytes. Remarkably, this CNS stem cell is present in both embryonic and adult mammalian (from rodent to human) brain. Recent evidence suggests that the adult human brain stem cells may be at the origin of the malignant human brain tumour – glioblastoma multiforme (glioma). Thus, the current research goal of the Weiss laboratory is to gain insights into the aberrant cell biology mechanisms of human brain tumour stem cells (BTSCs) that may lead to brain tumour initiation, therapeutic resistance and recurrence. During the past few years, we have established close to 100 BTSC lines from human glioma patients. These BTSC lines display many of the fundamental characteristics of stem cells such as ability to grow as neurospheres under serum-free conditions, multilineage differentiation and clonogenicity. Importantly, they maintain the key parental tumour mutations and mimic human tumour growth in vivo in orthotopic xenografts in NOD SCID mice. We were the first group to report the establishment of BTSC lines with endogenous expression of the IDH1 mutant enzyme and our BTSC library has lines with many of the key characteristic mutations reported in glioma. We employ a combination of cell biological, molecular, biochemical, and genomic approaches and use BTSCs as a model to study glioma biology and therapeutic response in vitro and in vivo. We are currently focused on four major areas of research: 1. The mechanisms of autocrine growth factor signalling in BTSCs leading to uncontrolled growth in brain tumours 2. The "stemness" factor - investigating the cell biology of BTSCs to understand disease initiation and recurrence 3. Intracellular oncogenic signalling pathways in BTSCs and a translational approach to experimental therapeutics and new drug therapy for brain tumours 4. Understanding BTSC metabolism with a special focus on the IDH1/2 mutation We believe the BTSC model system is a powerful tool to investigate human glioma biology and develop novel experimental therapeutics for the disease. Selected Publications: Luchman HA, Stechishin OD, Dang NH, Blough MD, Chesnelong C, Kelly JJ, Nguyen SA, Chan JA, Weljie AM, Cairncross JG, Weiss S. (2012) An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro-Oncology 14(2): 184-191. Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S, Travins J, Weiss S, Looper R, Ligon KL, Verhaak RGW, Yan H and Kaelin WG (2012) Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483:484-488. Chojnacki, A, Mak, G.K. and Weiss, S. (2011) PDGFRa expression distinguishes GFAP-expressing neural stem cells from PDGF-responsive neural precursors in the adult periventricular area. Journal of Neuroscience 31:9503-9512. Kelly JJ, Blough MD, Stechishin OD, Chan JA, Beauchamp D, Perizzolo M, Demetrick DJ, Steele L, Auer RN, Hader WJ, Westgate M, Parney IF, Jenkins R, Cairncross JG, Weiss S. (2010) Oligodendroglioma cell lines containing t(1;19)(q10;p10). Neuro-Oncology 12(7): 745-755 Kelly JJ, Stechishin O, Chojnacki A, Lun X, Sun B, Senger DL, Forsyth P, Auer RN, Dunn JF, Cairncross JG, Parney IF, Weiss S. (2009) Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens. Stem Cells 27(8):1722-1733. Chojnacki, A.K., Mak, G.K. and Weiss, S. (2009) Identity crisis for adult periventricular neural stem cells: subventricular zone astrocytes, ependymal cells or both? Nature Reviews Neuroscience 10:153-163. Reynolds, B.A. and Weiss, S. (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707-1710. CURRENT
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