Characterization of novel biomarkers in selecting for subtype specific medulloblastoma phenotypes.

Lisa Liang,Timothy Ryken,Nazanin Tatari,Vijay Ramaswamy,Magimairajan Issaivanan,Marc Remke,Marc R Del Bigio,Tamra E Werbowetski-Ogilvie,Christopher Aiken,Robyn Mcclelland,Ludivine Coudière Morrison,Michael D Taylor

doi:10.18632/oncotarget.6195

Abstract

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.

Highlights

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor
CD271, known as the p75 neurotrophin receptor (p75NTR) or nerve growth factor receptor (NGFR), is a transmembrane glycoprotein that plays a variety of roles in normal neurodevelopment including growth cone elongation, axon guidance, cell survival and cell death [22]
While this study focused on characterization of CD271, our results show that CD171 is a candidate for additional functional testing, as this cell surface marker has been linked with tumor progression, metastasis and therapeutic resistance in a wide variety of cancers [45,46,47,48,49,50,51,52,53]

Summary

Introduction

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. Primary tumors typically develop in the cerebellum and fourth ventricle; extensive dissemination through the cerebrospinal fluid often leads to metastasis and tumor recurrence [1]. We employed a high throughput flow cytometry screening platform to identify additional cell surface markers associated with stem/progenitor cell phenotypes in the SHH molecular variant.

Results

Conclusion