Cellular Senescence Promotes Malignant Brain Tumor Growth

Senescent cells act to suppress risk of cancer its very earliest stage. The pro-inflammatory secretions of cells made senescent as a result of mutational damage and the response of tumor suppressor genes attract the immune system to places in which damaged cells may give rise to a tumor. When senescent cells are present in larger numbers, and linger over time, as is the case in aged tissues, they actively encourage tumor growth, however. Here, researchers produce a compelling demonstration of this harmful consequence of cellular senescence, categorizing and eliminating senescent cells present in glioblastoma tumors in mice to slow tumor growth, and demonstrating similar characteristics in human glioblastoma cells.

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.

Link: https://doi.org/10.1038/s41467-023-36124-9

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