SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma.

G Carreno,J P Martinez-Barbera,C Stache,A Virasami,M Buchfelder,L Panousopoulos,T S Jacques,S P Robinson,R Guiho,J M Gonzalez-Meljem,L M Smith,L Chesler,J Apps,A Koers,S Haston,L S Danielson,J K R Boult

doi:10.1530/erc-18-0538

Abstract

Pharmacological inhibition of the sonic hedgehog (SHH) pathway can be beneficial against certain cancers but detrimental in others. Adamantinomatous craniopharyngioma (ACP) is a relevant pituitary tumour, affecting children and adults, that is associated with high morbidity and increased mortality in long-term follow-up. We have previously demonstrated overactivation of the SHH pathway in both human and mouse ACP. Here, we show that this activation is ligand dependent and induced by the expression of SHH protein in a small proportion of tumour cells. We investigate the functional relevance of SHH signalling in ACP through MRI-guided preclinical studies using an ACP mouse model. Treatment with vismodegib, a clinically approved SHH pathway inhibitor, results in a significant reduction in median survival due to premature development of highly proliferative and vascularised undifferentiated tumours. Reinforcing the mouse data, SHH pathway inhibition in human ACP leads to a significant increase in tumour cell proliferation both ex vivo, in explant cultures, and in vivo, in a patient-derived xenograft model. Together, our results demonstrate a protumourigenic effect of vismodegib-mediated SHH pathway inhibition in ACP.

Highlights

Adamantinomatous craniopharyngiomas (ACPs) are benign tumours of the sellar region that are associated with high morbidity and increased mortality in longterm follow-up
sonic hedgehog (SHH) protein is expressed in mouse and human ACP leading to the paracrine activation of the SHH pathway
Since mutations in the components of the SHH pathway have not been identified in humans (Brastianos et al 2014, Apps et al 2018) or mouse ACP (Gonzalez-Meljem et al 2017), our data suggest that the SHH pathway is activated in ACP in a ligand-dependent manner

Summary

Introduction

Adamantinomatous craniopharyngiomas (ACPs) are benign tumours of the sellar region that are associated with high morbidity and increased mortality in longterm follow-up. The expression of functionally equivalent mutant β-catenin in either pituitary embryonic precursors (Hesx1Cre/+;Ctnnb1lox(ex3)/+ mice) or adult pituitary stem cells (Sox2CerERT2/+;Ctnnb1lox(ex3)/+ mice) results in the formation of tumours resembling human ACP (Gaston-Massuet et al 2011, Andoniadou et al 2013). In both models, tumoural pituitaries show the presence of β-catenin-accumulating cells forming clusters, which share a common molecular signature with those found in humans (Gonzalez-Meljem et al 2017). The biological function of the SHH pathway in ACP pathogenesis remains unknown to date

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