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Selective vulnerability of the primitive meningeal layer to prenatal Smo activation for skull base meningothelial meningioma formation

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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References

  1. Louis DN, Ohgaki H, Wiestler OD. WHO classification of tumours of the Central Nervous System, Revised.. Fourth Edition. Lyon: International Agency for Research On Cancer; 2016.

    Google Scholar 

  2. Rogers L, Barani I, Chamberlain M, Kaley TJ, McDermott M, Raizer J, et al. Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review. J Neurosurg. 2015;122:4–23.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013;339:1077–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Clark VE, Harmancı AS, Bai H, Youngblood MW, Lee TI, Baranoski JF, et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet. 2016;48:1253–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Abedalthagafi M, Bi WL, Aizer AA, Merrill PH, Brewster R, Agarwalla PK, et al. Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro-Oncology. 2016;18:649–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Kros J, de Greve K, van Tilborg A, Hop W, Pieterman H, Avezaat C, et al. NF2 status of meningiomas is associated with tumour localization and histology. J Pathol. 2001;194:367–72.

    Article  PubMed  CAS  Google Scholar 

  7. Reuss DE, Piro RM, Jones DTW, Simon M, Ketter R, Kool M, et al. Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol. 2013;125:351–8.

    Article  PubMed  CAS  Google Scholar 

  8. Yuzawa S, Nishihara H, Yamaguchi S, Mohri H, Wang L, Kimura T, et al. Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system. Mod Pathol. 2016;29:708–16.

    Article  PubMed  CAS  Google Scholar 

  9. Jeong J, Mao J, Tenzen T, Kottmann AH, McMahon AP. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev. 2004;18:937–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Yoshida T, Vivatbutsiri P, Morriss-Kay G, Saga Y, Iseki S. Cell lineage in mammalian craniofacial mesenchyme. Mech Dev. 2008;125:797–808.

    Article  PubMed  CAS  Google Scholar 

  11. McBratney-Owen B, Iseki S, Bamforth SD, Olsen BR, Morriss-Kay GM. Development and tissue origins of the mammalian cranial base. Dev Biol. 2008;322:121–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Kalamarides M, Stemmer-Rachamimov AO, Niwa-Kawakita M, Chareyre F, Taranchon E, Han Z-Y, et al. Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes. Oncogene. 2011;30:2333–44.

    Article  PubMed  CAS  Google Scholar 

  13. Boetto J, Bielle F, Sanson M, Peyre M, Kalamarides M. SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro-Oncology. 2017;19:345–51. https://doi.org/10.1093/neuonc/now276

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D, et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 2006;66:10171–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Kalamarides M, Niwa-Kawakita M, Leblois H, Abramowski V, Perricaudet M, Janin A, et al. Nf2 gene inactivation in arachnoidal cells is rate-limiting for meningioma development in the mouse. Genes Dev. 2002;16:1060–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Marshall GM, Carter DR, Cheung BB, Liu T, Mateos MK, Meyerowitz JG, et al. The prenatal origins of cancer. Nat Rev Cancer. 2014;14:277–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Ellison DW, Dalton J, Kocak M, Nicholson SL, Fraga C, Neale G, et al. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 2011;121:381–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22:2454–72.

    Article  PubMed  CAS  Google Scholar 

  19. Xavier GM, Seppala M, Barrell W, Birjandi AA, Geoghegan F, Cobourne MT. Hedgehog receptor function during craniofacial development. Dev Biol. 2016;415:198–215.

    Article  PubMed  CAS  Google Scholar 

  20. Eberhart JK, Swartz ME, Crump JG, Kimmel CB. Early Hedgehog signaling from neural to oral epithelium organizes anterior craniofacial development. Dev Camb Engl. 2006;133:1069–77.

    CAS  Google Scholar 

  21. Sweeney RT, McClary AC, Myers BR, Biscocho J, Neahring L, Kwei KA, et al. Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nat Genet. 2014;46:722–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ohli J, Neumann JE, Grammel D, Schüller U. Localization of SHH medulloblastoma in mice depends on the age at its initiation. Acta Neuropathol. 2015;130:307–9.

    Article  PubMed  Google Scholar 

  23. Huttner HB, Bergmann O, Salehpour M, El Cheikh R, Nakamura M, Tortora A, et al. Meningioma growth dynamics assessed by radiocarbon retrospective birth dating. EBioMedicine. 2017;27:176–81.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kool M, Jones DTW, Jäger N, Northcott PA, Pugh TJ, Hovestadt V, ICGC PedBrain Tumor Project. et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25:393–405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Vitte J, Gao F, Coppola G, Judkins AR, Giovannini M. Timing of Smarcb1 and Nf2 inactivation determines schwannoma versus rhabdoid tumor development. Nat Commun. 2017;8:300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Samkari A, White J, Packer R. SHH inhibitors for the treatment of medulloblastoma. Expert Rev Neurother. 2015;15:763–70.

    Article  PubMed  CAS  Google Scholar 

  27. Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716–28.

    Article  PubMed  CAS  Google Scholar 

  28. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90–92.

    Article  PubMed  CAS  Google Scholar 

  29. Giovannini M, Robanus-Maandag E, van der Valk M, Niwa-Kawakita M, Abramowski V, Goutebroze L, et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 2000;14:1617–30.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Peyre M, Stemmer-Rachamimov A, Clermont-Taranchon E, Quentin S, El-Taraya N, Walczak C, et al. Meningioma progression in mice triggered by Nf2 and Cdkn2ab inactivation. Oncogene. 2013;32:4264–72.

    Article  PubMed  CAS  Google Scholar 

  31. Le Roux I, Konge J, Le Cam L, Flamant P, Tajbakhsh S. Numb is required to prevent p53-dependent senescence following skeletal muscle injury. Nat Commun. 2015;6:8528.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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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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Correspondence to Michel Kalamarides.

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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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