Characterization of novel biomarkers in selecting for subtype specific medulloblastoma phenotypes.
Major research efforts have focused on defining cell surface marker profiles for characterization and selection of brain tumor stem/progenitor cells. Medulloblastoma is the most common primary malignant pediatric brain cancer and consists of 4 molecular subgroups: WNT, SHH, Group 3 and Group 4. Given the heterogeneity within and between medulloblastoma variants, surface marker profiles may be subtype-specific. Here, we employed a high throughput flow cytometry screen to identify differentially expressed cell surface markers in self-renewing vs. non-self-renewing SHH medulloblastoma cells. The top 25 markers were reduced to 4, CD271/p75NTR/NGFR, CD106/VCAM1, EGFR and CD171/NCAM-L1, by evaluating transcript levels in SHH tumors relative to samples representing the other variants. However, only CD271/p75NTR/NGFR and CD171/NCAM-L1 maintain differential expression between variants at the protein level. Functional characterization of CD271, a low affinity neurotrophin receptor, in cell lines and primary cultures suggested that CD271 selects for lower self-renewing progenitors or stem cells. Moreover, CD271 levels were negatively correlated with expression of SHH pathway genes. Our study reveals a novel role for CD271 in SHH medulloblastoma and suggests that targeting CD271 pathways could lead to the design of more selective therapies that lessen the broad impact of current treatments on developing nervous systems.
Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Lisa
L
Liang
Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Christopher
C
Aiken
Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Robyn
R
McClelland
Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Ludivine Coudière
LC
Morrison
Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Nazanin
N
Tatari
Arthur and Sonia Labatt Brain Tumour Research Centre and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Marc
M
Remke
Arthur and Sonia Labatt Brain Tumour Research Centre and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Vijay
V
Ramaswamy
Cancer Care Manitoba (CCMB), Winnipeg, Manitoba, Canada.
Magimairajan
M
Issaivanan
Department of Neurosurgery, University of Kansas, Kansas City, Kansas, USA.
Timothy
T
Ryken
Department of Pathology, University of Manitoba and Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada.
Marc R
MR
Del Bigio
Arthur and Sonia Labatt Brain Tumour Research Centre and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Michael D
MD
Taylor
Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Tamra E
TE
Werbowetski-Ogilvie
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D008527:Medulloblastoma / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype
D014408:Biomarkers, Tumor
biomarkers; high-throughput flow cytometry; medulloblastoma; progenitors; self-renewal