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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / administration & dosage
  • Annexin A5 / genetics
  • Biomarkers, Tumor / genetics*
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Cell Survival / drug effects
  • Child
  • Enzyme Inhibitors / administration & dosage
  • Female
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Kaplan-Meier Estimate
  • MAP Kinase Kinase Kinase 1 / antagonists & inhibitors
  • Magnetic Resonance Angiography
  • Male
  • Medulloblastoma / drug therapy
  • Medulloblastoma / genetics*
  • Medulloblastoma / pathology
  • Nerve Tissue Proteins / genetics*
  • Prognosis*
  • Pyridines / administration & dosage
  • Receptors, Nerve Growth Factor / genetics*

Substances

  • Anilides
  • Annexin A5
  • Biomarkers, Tumor
  • Enzyme Inhibitors
  • HhAntag691
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Pyridines
  • Receptors, Nerve Growth Factor
  • MAP Kinase Kinase Kinase 1

Grant support