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PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth

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Abstract

Purpose

Gliomas are the most lethal adult primary brain cancers. Recent advances in their molecular characterization have contributed to a better understanding of their pathophysiology, but there is still a need to identify key genes controling glioma cell proliferation and differentiation. The p21-activated kinases PAK1 and PAK2 play essential roles in cell division and brain development and are well-known oncogenes. In contrast, the role of PAK3 in cancer is poorly understood. It is known, however, that this gene is involved in brain ontogenesis and has been identified as a gene of the proneural subtype signature in glioblastomas.

Methods

To better understand the role of PAK kinases in the pathophysiology of gliomas, we conducted expression analyses by querying multiple gene expression databases and analyzing primary human glioma samples. We next studied PAK3 expression upon differentiation in patient-derived cell lines (PDCLs) and the effects of PAK3 inhibition by lentiviral-mediated shRNA on glioma cell proliferation, differentiation and tumor growth.

Results

We show that contrary to PAK1 and PAK2, high PAK3 expression positively correlates with a longer survival of glioma patients. We also found that PAK3 displays differential expression patterns between glioma sub-groups with a higher expression in 1p/19q-codeleted oligodendrogliomas, and is highly expressed in tumors and PDCLs of the proneural subtype. In PDCLs, high PAK3 expression negatively correlated with proliferation and positively correlated with neuronal differentiation. Inhibition of PAK3 expression increased PDCL proliferation and glioma tumor growth in nude mice.

Conclusions

Our results indicate that PAK3 plays a unique role among PAKs in glioma development and may represent a potential therapeutic target.

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Acknowledgements

We thank OncoNeuroTek for sharing data and samples from their banks. We are also grateful to C. Levasseur for assistance in mice inoculation and to A. Bonilla, C. Dubois and C. Rousseau for animal care. We also acknowledge the technical support from the ICM facility iGenSeq.

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Authors and Affiliations

  1. Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, 91190, Gif-sur-Yvette, France

    Nathalie Magne, Véronique Rousseau, Kévin Duarte, Sandrine Poëa-Guyon & Jean-Vianney Barnier

  2. Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, 75013, Paris, France

    Vincent Gleize, Charlotte Schmitt, Ahmed Idbaih, Emmanuelle Huillard & Marc Sanson

  3. Normandie Univ, UNIROUEN, INSERM, U1239, Laboratoire Différenciation Et Communication Neuronale Et Neuroendocrine, Institut de Recherche Et D’Innovation Biomédicale de Normandie, 76000, Rouen, France

    Alexandre Mutel & Hélène Castel

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  1. Nathalie Magne
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Magne, N., Rousseau, V., Duarte, K. et al. PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth. Cell Oncol. 44, 1257–1271 (2021). https://doi.org/10.1007/s13402-021-00635-8

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