Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma

Cancer Cell. 2014 Jul 14;26(1):33-47. doi: 10.1016/j.ccr.2014.05.005. Epub 2014 Jun 19.

Abstract

Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox2(+) cells propagate sonic hedgehog subgroup medulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox2(+) cells produce rapidly cycling doublecortin(+) progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox2(+) cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox2(+) cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox2(+) cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox2(+) cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma.

MeSH terms

  • Animals
  • Antigens, Nuclear / metabolism
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Lineage
  • Cell Proliferation* / drug effects
  • Cerebellar Neoplasms / drug therapy
  • Cerebellar Neoplasms / genetics
  • Cerebellar Neoplasms / metabolism*
  • Cerebellar Neoplasms / pathology
  • DNA-Binding Proteins
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Medulloblastoma / drug therapy
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism*
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Molecular Sequence Data
  • Neoplasm Recurrence, Local
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis
  • Neuropeptides / metabolism
  • Nuclear Proteins / metabolism
  • Patched Receptors
  • Plicamycin / pharmacology
  • Prognosis
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*
  • Smoothened Receptor
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Antigens, Nuclear
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Hedgehog Proteins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • NeuN protein, mouse
  • Neuropeptides
  • Nuclear Proteins
  • Patched Receptors
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • SHH protein, human
  • SMO protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Sox2 protein, mouse
  • doublecortin protein
  • neuronal nuclear antigen NeuN, human
  • Plicamycin

Associated data

  • GENBANK/GSE48766
  • GENBANK/GSE50765