Targeting glioma stem cells through combined BMI1 and EZH2 inhibition

Abstract

Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile and hypoxic regions a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress, due to downregulation of the E3 ligase, RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are preferentially sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be necessary to overcome resistance to therapies caused by intratumoral heterogeneity.

Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF‐β1/Smad signaling pathway

“…GBM is characterized by complex tissue heterogeneity, in which there is a class of stem cell-like tumor-initiating cells, called GSCs, which have the ability to self-renew, grow continuously and differentiate into multiple neural cell types [34][35][36]. Further studies found that GSCs are key factors leading to the occurrence, recurrence, treatment tolerance and poor prognosis of glioma [35,[37][38][39][40]. We successfully propagated eight human GSC lines with four different molecular subtypes and found the highest PSAP expression and secretion in mesenchymal GSCs, as determined by western blotting and ELISA.…”

Targeting glioma stem‐like cell survival and chemoresistance through inhibition of lysine‐specific histone demethylase KDM2B

“…Widespread epigenetic reprogramming occurs during both stem cell differentiation and malignant transformation (Amente et al ., ). Recent findings indicate that chromatin dysregulation is likely to play a crucial role in GBM and the dependence of GSCs on epigenetic regulators offers an opportunity to target their self‐renewal capacity (Jin et al ., ; Miller et al ., ). Based on prior reports that GSCs are the most aggressive cellular population responsible for glioblastoma recurrence (Bao et al ., ; Rich, ) and the role of numerous KDMs in stem cell maintenance (Amente et al ., ; Andricovich et al ., ; He et al ., , ), we hypothesized specific function of KDM2B in GSCs.…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…Classifying GBMs into subtypes has focused on genetic signature at the whole‐tumor level, thereby simplifying the substantial intratumoral heterogeneity of GBMs. Independent studies have elucidated the differential gene expression patterns in distinct anatomic regions within a tumor . More specifically, the leading‐edge of GBMs was shown to display a proneural‐like signature, while the tumor core appeared more mesenchymal‐like .…”

“…102,103 More specifically, the leading-edge of GBMs was shown to display a proneural-like signature, while the tumor core appeared more mesenchymal-like. 103 The intratumoral heterogeneity of GBMs was further illustrated by cellular and genomic analysis at the single-cell level. Meyer and colleagues profiled individual tumorigenic clones from patient-derived GBM cells, identifying pre-existing clones harboring the potential to resist anti-tumor treatments such as TMZ.…”