Hedgehog signaling drives radioresistance and stroma-driven tumor repopulation in head and neck squamous cancers

Cancer Res. 2014 Dec 1;74(23):7024-36. doi: 10.1158/0008-5472.CAN-14-1346. Epub 2014 Oct 8.


Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with epithelial-to-mesenchymal transition, and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here, we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradiation, where it contributes to therapeutic inhibition. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Furthermore, radiotherapy-induced GLI1 expression was mediated in part by the mTOR/S6K1 pathway. Stroma exposed to radiotherapy promoted rapid tumor repopulation, and this effect was suppressed by Hh inhibition. Our results demonstrate that Gli1 that is upregulated at the tumor-stroma intersection in HNSCC is elevated by radiotherapy, where it contributes to stromal-mediated resistance, and that Hh inhibitors offer a rational strategy to reverse this process to sensitize HNSCC to radiotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology*
  • Carcinoma, Squamous Cell / radiotherapy
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / physiology
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology*
  • Head and Neck Neoplasms / radiotherapy
  • Hedgehog Proteins / metabolism*
  • Humans
  • Mice
  • Mice, Nude
  • Radiation Tolerance / physiology*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects
  • Squamous Cell Carcinoma of Head and Neck
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism*
  • Stromal Cells / pathology*
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Up-Regulation / drug effects
  • Veratrum Alkaloids / pharmacology
  • Zinc Finger Protein GLI1


  • GLI1 protein, human
  • Hedgehog Proteins
  • Transcription Factors
  • Veratrum Alkaloids
  • Zinc Finger Protein GLI1
  • MTOR protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • cyclopamine