Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma

Rana Salam, Alexa Saliou, Franck Bielle, Mathilde Bertrand, Christophe Antoniewski, Catherine Carpentier, Agusti Alentorn, Laurent Capelle, Marc Sanson, Emmanuelle Huillard, Léa Bellenger, Justine Guégan and Isabelle Roux ()
Additional contact information
Rana Salam: Genetics and Development of Brain Tumors Team
Alexa Saliou: Genetics and Development of Brain Tumors Team
Franck Bielle: Genetics and Development of Brain Tumors Team
Mathilde Bertrand: Data Analysis Core Platform
Christophe Antoniewski: Institut Français de Bioinformatique (IFB)
Catherine Carpentier: Genetics and Development of Brain Tumors Team
Agusti Alentorn: Genetics and Development of Brain Tumors Team
Laurent Capelle: Service de Neurochirurgie
Marc Sanson: Genetics and Development of Brain Tumors Team
Emmanuelle Huillard: Genetics and Development of Brain Tumors Team
Léa Bellenger: Institut Français de Bioinformatique (IFB)
Justine Guégan: Data Analysis Core Platform
Isabelle Roux: Genetics and Development of Brain Tumors Team

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells are identified in patient and mouse GBMs. Partial removal of p16Ink4a-expressing malignant senescent cells, which make up less than 7 % of the tumor, modifies the tumor ecosystem and improves the survival of GBM-bearing female mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identify the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM.

Date: 2023
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DOI: 10.1038/s41467-023-36124-9

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