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Cancer Res. 2018 Aug 15;78(16):4745-4759. doi: 10.1158/0008-5472.CAN-18-0027. Epub 2018 Jun 21.

CD271+ Cells Are Diagnostic and Prognostic and Exhibit Elevated MAPK Activity in SHH Medulloblastoma.

Author information

1
Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
2
Central Animal Care Services, University of Manitoba, Winnipeg, Manitoba, Canada.
3
Ottawa Bioinformatics Core Facility, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
4
Department of Pathology, University of Manitoba and the Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.
5
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
6
Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
7
Department of Neurosurgery, University of Kansas, Kansas City, Kansas.
8
The Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
9
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
10
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario Canada.
11
Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
12
The Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada. Tamra.Ogilvie@umanitoba.ca vijay.ramaswamy@sickkids.ca.
13
Division of Haematology/Oncology, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada.
14
Program in Neuroscience and Mental Health and Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.
15
Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada. Tamra.Ogilvie@umanitoba.ca vijay.ramaswamy@sickkids.ca.

Abstract

The extensive heterogeneity both between and within the medulloblastoma subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH medulloblastoma subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH medulloblastoma using IHC analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271+ and CD271- cells revealed molecularly distinct, coexisting cellular subsets, both in vitro and in vivo MAPK/ERK signaling was upregulated in the CD271+ population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration in vitro Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels in vivo, whereas, treatment with vismodegib, a well-known smoothened (SMO) inhibitor currently in clinical trials for the treatment of recurrent SHH medulloblastoma, had no significant effect in our models. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH medulloblastoma tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH medulloblastoma cells.Significance: This study identifies CD271 as a specific and novel biomarker of SHH-type medulloblastoma and that targeting CD271+ cells through MEK inhibition represents a novel therapeutic strategy for the treatment of SHH medulloblastoma. Cancer Res; 78(16); 4745-59. ©2018 AACR.

PMID:
29930101
DOI:
10.1158/0008-5472.CAN-18-0027
[Indexed for MEDLINE]
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