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A cadherin switch underlies malignancy in high-grade gliomas

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Abstract

Although the infiltrative behavior of malignant gliomas is one of their most critical aspects, the mechanisms underlying it have not yet been elucidated. To migrate in the brain parenchyma, malignant glioma cells need to bypass the cell–cell contact inhibitory signals. Here we propose that the blinding of cell–cell contact sensing in gliomas is caused by an unusual mechanism of cadherin switch, involving the replacement of N-cadherin with R-cadherin (Rcad) at the cell–cell junctions and the activation of ERK and p27. In our model of malignant glioma, we found that Rcad expression is necessary and sufficient to release cells from contact inhibition of proliferation, and is necessary, although not sufficient, for overriding contact inhibition of migration and for tumorigenicity. Altogether, these observations suggest that Rcad is a potential target for malignant glioma therapies.

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Acknowledgements

We thank Dr Magdalena Götz (Institute of Stem Cell Research-Helmholtz Centre Munich, Germany) for providing access to the time lapse equipment and Dr Masatoshi Takeichi (RIKEN Center for developmental biology, Kobe, Japan) for sharing plasmids. We acknowledge Dr Paola Briata, Dr Filippo Calzolari, Dr Federico Cremisi and Dr Roberto Gherzi for helpful comments on the manuscript. This work was supported by a NUSUG grant from AIRC, by the GR-2008-1135643 grant from Ministero della Salute, by Fondazione S. Paolo (Molecular and cellular basis of glioma) and by Fondazione CARIGE. ER salary was funded by the FIRC fellowship 9887.

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Author notes

  1. I Appolloni and M Barilari: These authors contributed equally to this work.

Authors and Affiliations

  1. U.O. Trasferimento Genico, IRCCS-AOU San Martino-IST, Largo Rosanna Benzi 10, Genoa, Italy

    I Appolloni, M Barilari, E Reisoli & P Malatesta

  2. Department of Experimental Medicine (DiMES), University of Genoa, Leon Battista Alberti 2, Genoa, Italy

    S Caviglia, E Gambini & P Malatesta

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  1. I Appolloni
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  2. M Barilari
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  4. E Gambini
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Correspondence to P Malatesta.

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Appolloni, I., Barilari, M., Caviglia, S. et al. A cadherin switch underlies malignancy in high-grade gliomas. Oncogene 34, 1991–2002 (2015). https://doi.org/10.1038/onc.2014.122

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