The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma
Nemanja Sarić, Matthew Selby, Vijay Ramaswamy, Marcel Kool, Brigitta Stockinger, Christer Högstrand, Daniel Williamson, Silvia Marino, Michael D. Taylor, Steven C. Clifford, M. Albert Basson
Abstract
Abstract Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancer-propagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr -deficient tumours and CPCs grown in vitro , showed elevated activation of the TGFβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr -deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor ( AHRR ) exhibited a significantly worse prognosis compared to AHRR low tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity.