The AHR pathway represses TGF\u03b2-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma

Nemanja Sarić,Silvia Marino,M Albert Basson,Michael D Taylor,Steven C Clifford,Brigitta Stockinger,Christer Hogstrand,Matthew Selby,Daniel Williamson,Marcel Kool,Vijay Ramaswamy

doi:10.1038/s41598-019-56876-z

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 AHRRlow 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.

Highlights

Medulloblastoma represents one of the most common forms of paediatric, malignant brain tumours accounting for around 20% of all paediatric tumours of the CNS1
To determine whether Ahr-deficient cells matured faster, primary granule cell progenitors (GCPs) were cultured in the absence of exogenous Sonic hedgehog (SHH) for six days in vitro and neurite length measured as an indicator of granule cell differentiation[27]
We identified a critical role for Ahr in preventing activation of the TGFβ mediator SMAD3, both in primary cerebellar GCPs and GCP-derived SHH meduloblastoma

Summary

Introduction

Medulloblastoma represents one of the most common forms of paediatric, malignant brain tumours accounting for around 20% of all paediatric tumours of the CNS1. Efforts to dissect the molecular underpinnings of medulloblastoma have identified four main subgroups - WNT, Sonic hedgehog (SHH), Group 3 and Group 4 - with distinct transcriptional, DNA methylation and mutational profiles, and different clinical characteristics and outcomes[5,6,7]. These subgroups are associated with different cells of origin[8]. Activation of the AHR pathway by endogenous ligands has been shown to promote brain cancers by the anti-tumour immune response[16], suggestive of context-dependent, multi-faceted roles for this pathway in cancer biology. Examination of the expression of AHR pathway genes in human medulloblastoma cohorts support an important role for the AHR pathway in SHH medulloblastoma biology

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Conclusion