Perspective of mesenchymal transformation in glioblastoma

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.The Paek laboratory is supported by the Korea Healthcare Technology R&D Project (Grant HI11C21100200, HI18C0886), funded by the Ministry of Health & Welfare, Republic of Korea; the Industrial Strategic Technology Development Program (Grant 10050154, Business Model Development for Personalized Medicine Based on Integrated Genome and Clinical Information) funded by the Ministry of Trade, Industry & Energy (MI, Korea); the Original Technol‑ogy Research Program for Brain Science through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant 2015M3C7A1028926, 2017M3C7A1044367); the Original Technology Research Program for Brain Science through the NRF funded by the Ministry of Education, Science and Technology (2017M3C7A1047392); the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (Grant Number: 2020M3A9G802202921)