期刊
ACTA NEUROPATHOLOGICA
卷 144, 期 6, 页码 1127-1142出版社
SPRINGER
DOI: 10.1007/s00401-022-02506-4
关键词
Proteomics; Glioblastoma; Immunosuppression; OAS2
资金
- CIHR Project Grant [PJT154357]
- NIH/NCI [P30CA016042, U24CA248265, P50CA211015]
- Ontario Ministry of Health and Long-Term Care
- Canadian Research Chair program
- TFRI [1065]
Glioblastoma (GBM) exhibits cellular and genetic heterogeneity, with a preferential transition from primary disease to recurrent disease towards a mesenchymal state. Immune regulatory/suppressive genes, particularly 2-5-oligoadenylate synthase 2 (OAS2), are identified as important drivers of recurrent GBM.
Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.
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