Abstract
Somatic activating mutations of smoothened (SMO), a component of the embryonic sonic hedgehog (SHH) signaling pathway, are found in 3–5% of grade I meningiomas, most of them corresponding to meningothelial meningiomas located at the anterior skull base. By generating different developmental stage-specific conditional activations in mice, we define a restricted developmental window during which conditional activation of Smo in Prostaglandin D2-synthase-positive mesoderm-derived meningeal layer of the skull base results in meningothelial meningioma formation. We show a selective vulnerability of the arachnoid from the skull base to Smo activation to initiate tumor development. This prenatal period and specific topography are correlated to the timing and location of SHH signaling involvement in the formation of craniofacial and meninges patterning, strongly corroborating the hypothesis of a developmental origin for Smo-activated meningiomas. Finally, we provide preclinical in vitro evidence of the efficacy of the SMO-inhibitor Sonidegib, supporting further preclinical and clinical evaluation of targeted treatment for refractory SMO-mutant meningiomas.
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Acknowledgements
We are grateful to Marco Giovannini for critical reviewing of the manuscript. We are indebted to Marine Giry and Amithys Rahimian (Onconeurotek) for technical assistance, and Veronique Parietti and Martine Chopin for mouse handling.
Funding:
This work was supported by a grant from the foundation ARC (PJA 20131200431), France. J.B. was funded by a grant from UM1 University, Montpellier, France.
Ethical approval:
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted, and all applicable national guidelines for the care and use of animals were followed.
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Boetto, J., Apra, C., Bielle, F. et al. Selective vulnerability of the primitive meningeal layer to prenatal Smo activation for skull base meningothelial meningioma formation. Oncogene 37, 4955–4963 (2018). https://doi.org/10.1038/s41388-018-0328-7
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DOI: https://doi.org/10.1038/s41388-018-0328-7
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