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Respective roles of Pik3ca mutations and cyproterone acetate impregnation in mouse meningioma tumorigenesis

Cancer Gene Therapy volume 30, pages 1114–1123 (2023)Cite this article

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Abstract

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.

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Fig. 1: Immunohistochemical characterization of progesterone receptors in mouse meninges.
Fig. 2: Kaplan–Meier cumulative survival curves.
Fig. 3: Pathological characterization of Pik3ca-induced meningiomas in mice.
Fig. 4: Pathological characterization of CPA-induced lesions in mice.
Fig. 5: Effect of Pik3ca mutations and CPA impregnation in meningeal cells in vitro.
Fig. 6: Exome sequencing of mammary tumors and meninges under cyproterone acetate impregnation.

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All data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

We would like to thank the ICMice for their help in mouse handling and husbandry, the iGenSaq platform for exome analysis and especially Agnes Rastetter for libraries prep and sequencing, the Histomics platform, and gratefully acknowledge Gareau Thomas at ICM Data Analysis Core for the bioinformatics analysis.

Funding

This work was supported by a grant from the Fondation ARC (PJA 20171206327) to MP and a grant from Fondation de France-ANR to MK. PCC was funded by a grant from Fondation ARC (M2R20180507186). TLV was funded by a grant from Dijon University.

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Author notes

  1. These authors contributed equally: Pierre-Cyril Cômes, Tuan Le Van.

Authors and Affiliations

  1. Sorbonne Université, CRICM INSERM U1127 CNRS UMR 7225, Paris Brain Institute, Paris, 75013, France

    Pierre-Cyril Cômes, Tuan Le Van, Suzanne Tran, Solène Huard, Samiya Abi-Jaoude, Pauline Marijon, Julien Boetto, Antoine Blouin, Franck Bielle, Yohan Ducos, Yu Teranishi, Michel Kalamarides & Matthieu Peyre

  2. Department of Neuropathology, AP-HP, Hôpital Pitié Salpétrière, Paris, 75013, France

    Suzanne Tran & Franck Bielle

  3. Université de Paris, Paris, 75006, France

    Quitterie Venot

  4. INSERM U1151, Institut Necker-Enfants Malades, Paris, 75015, France

    Quitterie Venot

  5. Department of Neurosurgery, AP-HP, Hôpital Pitié-Salpêtrière, Paris, 75013, France

    Pauline Marijon, Michel Kalamarides & Matthieu Peyre

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  1. Pierre-Cyril Cômes
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Contributions

MP was responsible for designing the study, conducting the experiments, interpreting results, and writing the first and final versions of the manuscript. PCC, TLV, ST, SH, SAJ, QV, PM, JB, AB, YT, and YD performed the experiments and interpreted the results. FB provided feedback and expertise on pathological analysis. MK contributed to the study design and critically reviewed the manuscript.

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Correspondence to Matthieu Peyre.

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Cômes, PC., Le Van, T., Tran, S. et al. Respective roles of Pik3ca mutations and cyproterone acetate impregnation in mouse meningioma tumorigenesis. Cancer Gene Ther 30, 1114–1123 (2023). https://doi.org/10.1038/s41417-023-00621-2

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