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Cellular prion protein (PrPC) in the development of Merlin-deficient tumours

Oncogene volume 36, pages 6132–6142 (2017)Cite this article

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Abstract

Loss of function mutations in the neurofibromatosis Type 2 (NF2) gene, coding for a tumour suppressor, Merlin, cause multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas. These tumours may occur sporadically or as part of the hereditary condition neurofibromatosis Type 2 (NF2). Current treatment is confined to (radio) surgery and no targeted drug therapies exist. NF2 mutations and/or Merlin inactivation are also seen in other cancers including some mesothelioma, breast cancer, colorectal carcinoma, melanoma and glioblastoma. To study the relationship between Merlin deficiency and tumourigenesis, we have developed an in vitro model comprising human primary schwannoma cells, the most common Merlin-deficient tumour and the hallmark for NF2. Using this model, we show increased expression of cellular prion protein (PrPC) in schwannoma cells and tissues. In addition, a strong overexpression of PrPC is observed in human Merlin-deficient mesothelioma cell line TRA and in human Merlin-deficient meningiomas. PrPC contributes to increased proliferation, cell-matrix adhesion and survival in schwannoma cells acting via 37/67 kDa non-integrin laminin receptor (LR/37/67 kDa) and downstream ERK1/2, PI3K/AKT and FAK signalling pathways. PrPC protein is also strongly released from schwannoma cells via exosomes and as a free peptide suggesting that it may act in an autocrine and/or paracrine manner. We suggest that PrPC and its interactor, LR/37/67 kDa, could be potential therapeutic targets for schwannomas and other Merlin-deficient tumours.

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Acknowledgements

We thank Mario Salmona for mock PrP peptide and Joseph Testa for Merlin adenovirus. This work was supported by The Laura Crane Youth Cancer Trust and Brain Tumour Research.

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Author notes

  1. S Ammoun and C O Hanemann: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK

    L Provenzano, Y Ryan, J Lyons-Rimmer, F Dave, E A Maze, C L Adams, S Ammoun & C O Hanemann

  2. Department of Cellular and Anatomical Pathology, Derriford Hospital, Plymouth, UK

    D A Hilton & R Rigby-Jones

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  1. L Provenzano
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  2. Y Ryan
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Correspondence to S Ammoun.

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Provenzano, L., Ryan, Y., Hilton, D. et al. Cellular prion protein (PrPC) in the development of Merlin-deficient tumours. Oncogene 36, 6132–6142 (2017). https://doi.org/10.1038/onc.2017.200

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