title: Hedgehog signaling drives radioresistance and stroma-driven tumor repopulation in head and neck squamous cancers.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Gan
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Justin
authors.initials: J
authors.lastname: Eagles
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Keysar
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Magdalena J
authors.initials: MJ
authors.lastname: Glogowska
authors.affiliation: Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Cem
authors.initials: C
authors.lastname: Altunbas
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Anderson
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Phuong N
authors.initials: PN
authors.lastname: Le
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: J Jason
authors.initials: JJ
authors.lastname: Morton
authors.affiliation: Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Barbara
authors.initials: B
authors.lastname: Frederick
authors.affiliation: Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado. Charles C. Gates Center for Stem Cell Biology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado. Charles C. Gates Center for Stem Cell Biology, University of Colorado School of Medicine, Aurora, Colorado. Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado. Antonio.Jimeno@ucdenver.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011836:Radiation Tolerance / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; C000541:cyclopamine