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

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 were identified in patient and mouse GBMs. Partial removal of p16Ink4a-expressing malignant senescent cells, which make up less than 7 % of the tumor, modified the tumor ecosystem and improved the survival of GBM-bearing mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identified 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.

New insights into the Immune TME of adult-type diffuse gliomas

“…Efforts are currently underway to better characterize TAM subtypes, ligand–receptor pairs, and immune checkpoints expressed by these cells [ 66 ]. It is becoming clear that glioblastoma progression requires not only genetic drivers but also microenvironment interactions [ 9 ▪▪ , 10 ▪▪ , 11 ▪ , 67 ▪ ]. While most of the work on immunoevading mechanisms and myeloid interactions has been done in MES-like gliomas [ 13 ▪ , 14 ▪ , 18 , 67 ▪ ], the immunomodulatory mechanisms operating in low-grade and IDH-mutant gliomas remain largely unknown.…”

“…Multiomics analyses of glioma cells at single-cell resolution revealed that intratumoral epigenetic diversity (but not genomic alterations alone) accounts for adaptive changes to environmental stimuli such as hypoxia and irradiation, leading to cell-state transitions [ 8 ▪ , 9 ▪▪ ]. Additional characterization of glioblastomas by spatially resolved transcriptomics showed that inflammation and hypoxia, as well as changes in metabolic activity and the neural environment contribute to the transcriptional heterogeneity that characterizes the four cellular archetypes [ 11 ▪ ]. In particular, expression of potassium channels and metabotropic glutamate receptors are important for the transition between OPC-like and NPC-like tumors, whereas hypoxia leads to genomic instability in MES-like subtype [ 10 ▪▪ ].…”

“…Moreover, age-related changes in the neural environment promote enrichment in the MES-like subtype [ 10 ▪▪ ], a finding consistent with the fact that age is the main risk factor for glioblastoma development. Senescence in malignant cells also contributes to the development and heterogeneity of these tumors [ 11 ▪ , 12 ▪ ]. Of note, a transcriptional signature of senescence correlated with poor prognosis in human patients, whereas treatments with a senolytic agent improved the survival of mice bearing gliomas [ 11 ▪ ], and efficiently eliminated preirradiated tumors [ 12 ▪ ].…”

“…Senescence in malignant cells also contributes to the development and heterogeneity of these tumors [ 11 ▪ , 12 ▪ ]. Of note, a transcriptional signature of senescence correlated with poor prognosis in human patients, whereas treatments with a senolytic agent improved the survival of mice bearing gliomas [ 11 ▪ ], and efficiently eliminated preirradiated tumors [ 12 ▪ ]. Therefore, targeting of senescent cells appears as a novel therapeutic option.…”

Cellular senescence in cancer: clinical detection and prognostic implications

“…However, in certain tumor types, the (abundant) presence of OIS or expression of senescence-associated markers is also linked to worse prognosis [132,197,221,237,238,248]. Perhaps even more surprisingly, both absence and extensive presence of senescence in CRC was associated with negative prognosis whereas moderate presence was associated with the best prognosis [174], demonstrating that an extensive senescence burden can paradoxically impair clinical outcome in contrast to a moderate senescence burden.…”