Department of Neurosurgery, Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.
The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.
Acta Neuropathol Commun. 2021 Mar 24;9(1):50. doi: 10.1186/s40478-021-01151-4.
Despite aggressive multimodal treatment, glioblastoma (GBM), a grade IV primary brain tumor, still portends a poor prognosis with a median overall survival of 12-16 months. The complexity of GBM treatment mainly lies in the inter- and intra-tumoral heterogeneity, which largely contributes to the treatment-refractory and recurrent nature of GBM. By paving the road towards the development of personalized medicine for GBM patients, the cancer genome atlas classification scheme of GBM into distinct transcriptional subtypes has been considered an invaluable approach to overcoming this heterogeneity. Among the identified transcriptional subtypes, the mesenchymal subtype has been found associated with more aggressive, invasive, angiogenic, hypoxic, necrotic, inflammatory, and multitherapy-resistant features than other transcriptional subtypes. Accordingly, mesenchymal GBM patients were found to exhibit worse prognosis than other subtypes when patients with high transcriptional heterogeneity were excluded. Furthermore, identification of the master mesenchymal regulators and their downstream signaling pathways has not only increased our understanding of the complex regulatory transcriptional networks of mesenchymal GBM, but also has generated a list of potent inhibitors for clinical trials. Importantly, the mesenchymal transition of GBM has been found to be tightly associated with treatment-induced phenotypic changes in recurrence. Together, these findings indicate that elucidating the governing and plastic transcriptomic natures of mesenchymal GBM is critical in order to develop novel and selective therapeutic strategies that can improve both patient care and clinical outcomes. Thus, the focus of our review will be on the recent advances in the understanding of the transcriptome of mesenchymal GBM and discuss microenvironmental, metabolic, and treatment-related factors as critical components through which the mesenchymal signature may be acquired. We also take into consideration the transcriptomic plasticity of GBM to discuss the future perspectives in employing selective therapeutic strategies against mesenchymal GBM.
尽管采用了积极的多模式治疗，胶质母细胞瘤（GBM）仍是一种 4 级原发性脑肿瘤，中位总生存期为 12-16 个月，预后仍然较差。GBM 治疗的复杂性主要在于肿瘤内和肿瘤间的异质性，这在很大程度上导致了 GBM 的治疗抵抗和复发。通过为 GBM 患者开发个性化药物铺平道路，癌症基因组图谱将 GBM 分为不同转录亚型的分类方案被认为是克服这种异质性的一种宝贵方法。在确定的转录亚型中，间充质亚型与更具侵袭性、血管生成、缺氧、坏死、炎症和多疗法耐药的特征相关，比其他转录亚型更为明显。因此，当排除高转录异质性患者时，间充质 GBM 患者的预后比其他亚型差。此外，鉴定主间质调节因子及其下游信号通路不仅增加了我们对间充质 GBM 复杂调控转录网络的理解，而且还为临床试验生成了一系列有效的抑制剂。重要的是，GBM 的间质转化与治疗诱导的复发性表型变化密切相关。总之，这些发现表明，阐明间充质 GBM 的调控和可塑性转录组特性对于开发新的、选择性的治疗策略至关重要，这可以改善患者的护理和临床结果。因此，我们的综述重点将放在对间充质 GBM 转录组的理解的最新进展上，并讨论微环境、代谢和治疗相关因素作为间充质特征可能获得的关键组成部分。我们还考虑了 GBM 的转录组可塑性，讨论了针对间充质 GBM 采用选择性治疗策略的未来前景。
