Driving mesenchymal transition in glioblastoma

See the article by Song and Jiang et al in this issue, pp. 46–57.

Intratumoral heterogeneity is a particular challenge for the treatment of glioblastoma.¹ Since initial transcriptomic analyses uncovered distinct molecular subtypes in primary glioblastoma—namely classical, proneural, and mesenchymal²—and subsequent single cell sequencing analyses have demonstrated the coexistence of multiple molecular cellular states within one tumor,³ many studies have focused on the central drivers of this cellular and molecular plasticity. Recently, more sophisticated transcriptomic and epigenetic profiling on the single cell level has supported a model in which glioblastoma stem cells (GSCs) in a given tumor transition between different states defined by the molecular subtype,⁴ and these states are differentially defined by key genetic alterations and the tumor microenvironment.⁵ This model explains not only the inherent resistance of these tumors to conventional genotoxic treatments⁶ but also the striking stability of clonal diversity in recurrent disease.⁷ As proneural-to-mesenchymal transition is believed to be a hallmark of resistance in recurrent tumors and driven mainly by microenvironmental factors, such as hypoxia and aberrant glycolysis, a detailed understanding of the molecular mechanisms may provide the key for targeted therapeutic interventions preventing recurrence and allowing exploitation of molecular vulnerabilities.⁸

In this issue of Neuro-Oncology, Song et al. identify nuclear factor of activated T cells (NFAT)2 as a hallmark of mesenchymal glioblastoma.⁹ NFAT2 is a key transcription factor and master regulator of cytokine production and effector function of activated T cells.¹⁰ Its function has recently been expanded to regulation of key cellular processes in many cell types, including the malignant phenotype of cancer cells.¹¹ In their study, NFAT2 expression correlated with a mesenchymal phenotype and poor prognosis. More importantly, functional analyses in GSCs demonstrated that NFAT2 promotes mesenchymal transition. The study further identifies histone deacetylase complex (HDAC)1 as a key target of NFAT2 in GSC. HDAC1 correlates with NFAT2 in glioblastoma gene expression datasets and is capable of restoring mesenchymal transition in GSCs devoid of NFAT2. These findings strongly suggest the NFAT2-HDAC1 pathway to be critically involved in maintaining the malignant phenotype and promoting mesenchymal transition in GSCs.

As NFAT2 is a master regulator of immune reactivity not only in T cells, this study supports the current concept that mesenchymal transition in glioblastoma is driven mainly by the microenvironment, particularly infiltrating myeloid cells representing the largest nontumor cellular compartment in glioblastoma.¹² But what are the therapeutic implications for patients and clinical trial design? NFAT2 is a target of calcineurin; inhibitors of this pathway are potent immunosuppressive agents and may thus amplify an unwanted hallmark of glioblastoma.¹³ HDAC1, which the authors have demonstrated to be critically involved in regulating mesenchymal transition in their study, may offer a more viable therapeutic target. Phase I/II clinical trials thus far have not demonstrated efficacy of HDAC inhibitors in unselected newly diagnosed recurrent glioblastoma when combined with genotoxic and/or anti-angiogenic therapy.^14–16 Post-hoc analyses have identified transcriptional signatures containing immune-related genes associated with a clinical benefit.¹⁵ While it is tempting to speculate that mesenchymal glioblastoma may respond to HDAC inhibition, a prerequisite for further development in this area is a proof of concept ideally from ongoing adaptive clinical trials evaluating molecularly matched targeted therapies.^17,18 Functionally relevant pathways such as NFAT2-HDAC1 can serve as a biomarker for selecting patients responding to HDAC inhibitors.