Perspective of mesenchymal transformation in glioblastoma

Abstract

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.

Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment

“…We showed that the proneural-to-mesenchymal transition is independent of histological feature composition and reflects transcriptional changes in the cellular tumor. Mesenchymal transitions have been shown to associate with several factors, including increased myeloid cell infiltration, radiation-induced NF-κB activation, altered tumor metabolism, and hypoxia (Bhat et al, 2013;Garofano et al, 2021;Kim et al, 2021;Mao et al, 2013;Osuka et al, 2021;Schmitt et al, 2021;Wang et al, 2017). Our results indicate that the proneural-tomesenchymal transition is likely influenced by tumor-wide changes, supporting the hypothesis that this transition is involved in therapy resistance.…”

“…The mesenchymal subtype of glioma is associated with increased accumulation of immune cells, primarily of the myeloid lineage (Bhat et al, 2013;Kim et al, 2021;Wang et al, 2017). We thus hypothesized that interactions between the tumor-infiltrating myeloid cells and malignant cells can influence the tumor's trajectory at recurrence.…”

Spatiotemporal analysis of glioma heterogeneity reveals Col1A1 as an actionable target to disrupt tumor mesenchymal differentiation, invasion and malignancy

“…Mesenchymal transformation is a hallmark of tumor heterogeneity that has been associated with a more aggressive phenotype and therapeutic resistance 13,15,18 . Mesenchymal transformation involves fibroblast-like morphological changes associated with active migration and gain of expression of mesenchymal genes as previously described 18,19 .…”

“…Integrating morphological features, spatially resolved transcriptomics, and cellular dynamics resulting from mesenchymal transformation, growth, and invasion are thus of great relevance to our understanding of glioma progression 13,20 .…”

Radioresistance of Human Cancers: Clinical Implications of Genetic Expression Signatures

“…Transcriptomic, methylation, mutational and mesenchymal signatures following radiotherapy all have been reported to correlate with patient's prognosis in glioblastoma (GBM) (168)(169)(170)(171)(172). For example, gene signatures focusing on mesenchymal traits, which can be induced by radiation, distinctively correlate with worse prognosis (173). Within this present study, upregulation of the Epithelia Mesenchymal Transition gene set was only correlated with a worse prognosis in CESC patients, highlighting the importance of distinct approaches for each tumor type, and even tumor subtype.…”