Astrocytes promote medulloblastoma progression through hedgehog secretion

Yongqiang Liu, Larra W. Yuelling, Yuan Wang, Fang Du, Renata E. Gordon, Jenny A. O'Brien, Jessica M.Y. Ng, Shannon Robins, Eric H. Lee, Hailong Liu, Tom Curran, Zeng Jie Yang

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Astrocytes, the most abundant type of glial cells in the brain, play critical roles in supporting neuronal development and brain function. Although astrocytes have been frequently detected in brain tumors, including medulloblastoma (MB), their functions in tumorigenesis are not clear. Here, we demonstrate that astrocytes are essential components of the MB tumor microenvironment. Tumor-associated astrocytes (TAA) secrete the ligand sonic hedgehog (Shh), which is required for maintaining MB cell proliferation despite the absence of its primary receptor Patched-1 (Ptch1). Shh drives expression of Nestin in MB cells through a smoothened-dependent, but Gli1-independent mechanism. Ablation of TAA dramatically suppresses Nestin expression and blocks tumor growth. These findings demonstrate an indispensable role for astrocytes in MB tumorigenesis and reveal a novel Ptch1-independent Shh pathway involved in MB progression.

Original languageEnglish
Pages (from-to)6692-6703
Number of pages12
JournalCancer Research
Volume77
Issue number23
DOIs
StatePublished - Dec 1 2017

Keywords

  • Animals
  • Astrocytes/metabolism
  • Carcinogenesis/pathology
  • Cell Proliferation/physiology
  • Cells, Cultured
  • Cerebellar Neoplasms/pathology
  • Hedgehog Proteins/metabolism
  • Medulloblastoma/pathology
  • Mice
  • Mice, Transgenic
  • Nestin/biosynthesis
  • Patched-1 Receptor/metabolism
  • Smoothened Receptor/metabolism
  • Tumor Microenvironment/physiology
  • Zinc Finger Protein GLI1/metabolism

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