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 (EMT) 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 irradition where it contributes to therapy resistance. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Further, 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 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.

Impact of Sonic Hedgehog Pathway Expression on Outcome in HPV Negative Head and Neck Carcinoma Patients after Surgery and Adjuvant Radiotherapy

“…Studies showed that Gli-1 acts as a promoter as well as a transcriptional repressor of E-cadherin, an epithelial marker of de-differentiation, whereas the particular functions of different isoforms of Gli-1 have not been elucidated yet [34]. Contrasting our study, Gan and colleagues described contribution to radioresistance by Gli-1 in an in-vitro tumor model [35]. It has also been shown that Gli-2 expression was associated with cell death in mice that were treated with radiation therapy for intrahepatic carcinoma [36].…”

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

“…32,33 However, transient Hh activation in salivary glands, such as overexpression of Gli1 transgene for 15 weeks and overexpression of Shh transgene for 1 week, did not result in any detectable tumor in mice. 15,34 Gene therapy for salivary gland hypofunction has several unique advantages, including easy access to most parenchymal cells via duct cannulation, the capacity to produce high amounts of protein, and tight encapsulation that minimizes concern about transgene spread.…”

Targeting Head and Neck Cancer Stem Cells

“…These investigations show increased response to radiation in CSCs after inhibition of CHEK1/2 and application of ATRA (Bertrand et al 2014). Inhibition of SHH/MTOR/RPS6KB1 pathways leads to increased radiosensitivity in CSCs, suggesting a role for these pathways and potential targetable options for increasing CSC radiosensitivity (Gan et al 2014).…”