Brain Tumour Stem Cell Biology and Experimental Therapeutics
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.
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.
and Weiss, S. (1992) Generation of neurons and astrocytes from isolated
cells of the adult mammalian central nervous system. Science 255:1707-1710.
Terry Fox Cancer Research Institute
Network of Centres of Excellence – Stem Cell Network
Alberta Cancer Foundation
Canadian Institutes of Health Research (CIHR)
Tel: (403) 220-3558
Dr. Artee Luchman (Research Assistant Professor) / (Manager Brain
Tumour Stem Cell Core)
Rozina Hassam (Lab Manager)
Dorothea Livingstone (Technician)
Orsolya Cseh (Technician)
Akpevwe Onoyovwi (Technician)
Dr. Carlo Cusulin (PDF)
Stephanie Nguyen (M.Sc student)
Braden Teitge (M.Sc / MD student)
Charles Chesnelong (PhD student)