Centre for Discovery in Cancer Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Acta Neuropathol. 2022 Dec;144(6):1127-1142. doi: 10.1007/s00401-022-02506-4. Epub 2022 Sep 30.
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.
胶质母细胞瘤（GBM）的特征是广泛的细胞和遗传异质性。其作为原发性疾病（pGBM）的初始表现已经进行了详尽的分子和细胞分析。相比之下，我们对 GBM 如何进化以逃避治疗的选择压力的理解却非常有限。复发性 GBM（rGBM）的蛋白质组景观，对大多数用于治疗 pGBM 的治疗方法都具有抗药性，我们知之甚少。因此，我们对 134 例患者来源的 pGBM 和 rGBM 样本进行了转录组和蛋白质组定量分析，其中包括 40 对匹配的 pGBM-rGBM 样本。GBM 亚型从 pGBM 向 rGBM 转变，在复发时向更偏向间充质的状态转变，这与 rGBM 的侵袭性越来越强相一致。我们发现免疫调节/抑制基因是 rGBM 的重要驱动因素，特别是 2-5-寡聚腺苷酸合成酶 2（OAS2）是复发性疾病的必需基因。我们的数据确定了一类新的治疗靶点，它们是 pGBM 对治疗的适应性反应中产生的，特别是在复发性疾病中出现，并且可能在 pGBM 诊断时不存在新的治疗机会。
