SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma
Carreno G, Boult JKR, Apps J, Gonzalez-Meljem JM, Haston S, Guiho R, Stache C, Danielson LS, Koers A, Smith LM, Virasami A, Panousopoulos L, Buchfelder M, Jacques TS, Chesler L, Robinson SP, Martinez-Barbera JP (2019)
Publication Type: Journal article
Publication year: 2019
Journal
Book Volume: 26
Pages Range: 355-366
Journal Issue: 3
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 magnetic resonance imaging (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.
Authors with CRIS profile
Involved external institutions
University College London (UCL)
United Kingdom (GB)
The Institute of Cancer Research (ICR)
United Kingdom (GB)
Great Ormond Street Hospital (GOSH)
United Kingdom (GB)
United Kingdom (GB)
The Institute of Cancer Research (ICR)
United Kingdom (GB)
Great Ormond Street Hospital (GOSH)
United Kingdom (GB)
How to cite
APA:
Carreno, G., Boult, J.K.R., Apps, J., Gonzalez-Meljem, J.M., Haston, S., Guiho, R.,... Martinez-Barbera, J.P. (2019). SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma. Endocrine-Related Cancer, 26(3), 355-366. https://dx.doi.org/10.1530/ERC-18-0538
MLA:
Carreno, G., et al. "SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma." Endocrine-Related Cancer 26.3 (2019): 355-366.
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