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.

Keywords: Glioblastoma; Master transcriptional regulator; Mesenchymal transition; TAMs; Transcriptomic plasticity.

Fig. 1

The impact of microenvironmental factors on shaping GBM transcriptome. Mesenchymal transition may be induced by a variety of microenvironmental factors such as a interaction between GBM cells and tumor-associated macrophages/microglia b proinflammatory processes induced by radiation c hypoxia and d astrocytes. As depicted in the figure, GBM is a highly heterogeneous tumor consisting of several cellular entities, such as fibroblasts, immune cells, and astrocytes and also of GBM cells harboring different transcriptomic signatures. For the representation of GBM cells with the distinctive transcriptomic states, only mesenchymal and proneural cells are portrayed

Fig. 2

The impact of metabolic factors on shaping GBM transcriptome. Metabolic alterations associated with the mesenchymal signature of GBM. The three possible sources of lactate in GBM tumor are mesenchymal GBM cells, necrotic GBM cells, and macrophages/microglia present in the microenvironment of the tumor. Compared to GBMs of other transcriptional subtypes, mesenchymal GBM is characterized by a high production rate of lactate, which intensifies the acidity of the tumor microenvironment. Furthermore, the interaction between GBM cells and the attracted macrophages/microglia further promotes the mesenchymal property of the tumor

Fig. 3

Treatment-induced proneural-to-mesenchymal transition. a Pre-operative tumor of proneural subtype. The tumor consists of more proneural GBM cells than mesenchymal cells. Also, the necrotic core of the tumor is shown containing hypoxic and necrotic GBM cells along with astrocytes and macrophages/microglia. b Post-operative state of the tumor region. Residual tumor and stromal cells remain beyond the margins after surgical resection. Such residual cells would then experience therapeutic stresses from various kinds of treatments, including radiation, chemotherapy and antiangiogenic therapy, and may be associated with treatment-induced mesenchymal transformation of the tumor. c Post-therapeutic tumor of mesenchymal subtype. The tumor contains more mesenchymal GBM cells than proneural cells. The recurrent tumor is extensively vascularized than the primary tumor, as newly formed blood vessels are highly branched