Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

Abstract

Despite decades of research, glioblastoma (GBM) remains invariably fatal among all forms of cancers. The high level of inter- and intratumoral heterogeneity along with its biological location, the brain, are major barriers against effective treatment. Molecular and single cell analysis identifies different molecular subtypes with varying prognosis, while multiple subtypes can reside in the same tumor. Cellular plasticity among different subtypes in response to therapies or during recurrence adds another hurdle in the treatment of GBM. This phenotypic shift is induced and sustained by activation of several pathways within the tumor itself, or microenvironmental factors. In this review, the dynamic nature of cellular shifts in GBM and how the tumor (immune) microenvironment shapes this process leading to therapeutic resistance, while highlighting emerging tools and approaches to study this dynamic double-edged sword are discussed.

Keywords: clinical outcome; glioblastoma (GBM); mesenchymal transition; molecular subtypes; therapy responses; tumor microenvironment.

Figure 1

TCGA analysis for distribution of GBM subtypes at diagnosis and their associated markers.

Figure 2

The regulatory mechanisms involved in GBM MES transformation . Extracellular soluble factors (such as interleukin 8 (IL8), tumor necrosis factor‐α (TNFα), transforming growth factor beta (TGFβ), and Wnt) bind to their respective receptors on GBM cells and induce MES transition by initiating a cascade of molecular events. Epigenetic reprogramming [enhancer of zeste homolog 2 (EZH2), zinc finger, and BTB domain containing 18 (ZBTB18)] modulate MES transition by direct binding to DNA molecules. MicroRNAs (miRNAs) and long noncoding RNAs (LNC) can also contribute to MES transition by modulating their target. Intermediate molecules: nuclear factor kappa light chain enhancer of activated B cells (NF‐κB), Smad family member 2 (Smad2), pyruvate dehydrogenase kinase 1 (PDK1)/proto‐oncogene c‐JUN (c‐JUN); Transcription factors: tafazzin (TAZ), signal transducer and activator of transcription 3 (STAT3) and CCAAT enhancer binding protein beta (C/EBP‐β), zinc finger protein SNAI (SNAI), zinc finger protein SNAI2 (SLUG), zinc finger E‐box‐binding homeobox (ZEB), twist‐related protein (TWIST).

Figure 3

Immune microenvironment triggers MES signature in GBM. A bilateral interaction between GBM and tumor associated macrophages/microglia (TAMs) through soluble factors and other regulatory mechanisms can induce mesenchymal transformation. MES tumors are characterized by the presence of different types of T‐cells, neutrophils, macrophages, and microglia. On the other hand, natural killer (NK) cells and tumor‐infiltrating lymphocytes (TILs) are predominant in PN tumors.

Figure 4

Summary of available tools/strategies to study MES signature/transition in GBM. A) Mesenchymal signature are typically evaluated by in vitro (2D and 3D culture) and in vivo (PDX and patient tissues) models; B,C) Omics (transcriptomics and proteomics) and immunohistochemistry (IHC) are gold standard tests to study cellular heterogeneity in GBM. Different assays to assess GBM MES signature: D) cellular barcoding where each transformed cell harbor a unique and heritable genetic tag is analyzed by single‐cell analysis; E) Cre‐Loxp system where Cre is cloned under a MES‐specific promoter and upon MES transition and Cre expression, cells switch from red to green; F) chromobody‐based imaging where a MES‐specific nanobody is fused to a reporter gene (chromobody) and is expressed in the cells upon MES transition.