Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Remote neuronal activity drives glioma progression through SEMA4F.

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy.

Overcoming metabolic stress is a critical step in tumor growth. Acetyl coenzyme A (acetyl-CoA) generated from glucose and acetate uptake is important for histone acetylation and gene expression. However, how acetyl-CoA is produced under nutritional stress is unclear. We demonstrate here that glucose deprivation results in AMP-activated protein kinase (AMPK)-mediated acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659, which exposed the nuclear localization signal of ACSS2 for importin α5 binding and nuclear translocation. In the nucleus, ACSS2 binds to transcription factor EB and translocates to lysosomal and autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and promote lysosomal biogenesis, autophagy, cell survival, and brain tumorigenesis. In addition, ACSS2 S659 phosphorylation positively correlates with AMPK activity in glioma specimens and grades of glioma malignancy. These results underscore the significance of nuclear ACSS2-mediated histone acetylation in maintaining cell homeostasis and tumor development.

Sox9 directs divergent epigenomic states in brain tumor subtypes.

Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZRFUS) EPN growth and diminishing H3K27ac states. These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG and an association with the ZRFUS oncofusion in EPN. Mechanistic studies revealed extensive Sox9 and ZRFUS promoter co-occupancy, indicating functional synergy in promoting EPN tumorigenesis. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.

CXCR4 expression is associated with proneural-to-mesenchymal transition in glioblastoma.

Glioblastoma (GBM) is the most common primary intracranial malignant tumor and consists of three molecular subtypes: proneural (PN), mesenchymal (MES) and classical (CL). Transition between PN to MES subtypes (PMT) is the glioma analog of the epithelial-mesenchymal transition (EMT) in carcinomas and is associated with resistance to therapy. CXCR4 signaling increases the expression of MES genes in glioma cell lines and promotes EMT in other cancers. RNA sequencing (RNAseq) data of PN GBMs in The Cancer Genome Atlas (TCGA) and secondary high-grade gliomas (HGGs) from an internal cohort were examined for correlation between CXCR4 expression and survival as well as expression of MES markers. Publicly available single-cell RNA sequencing (scRNAseq) data was analyzed for cell type specific CXCR4 expression. These results were validated in a genetic mouse model of PN GBM. Higher CXCR4 expression was associated with significantly reduced survival and increased expression of MES markers in TCGA and internal cohorts. CXCR4 was expressed in immune and tumor cells based on scRNAseq analysis. Higher CXCR4 expression within tumor cells on scRNAseq was associated with increased MES phenotype, suggesting a cell-autonomous effect. In a genetically engineered mouse model, tumors induced with CXCR4 exhibited a mesenchymal phenotype and shortened survival. These results suggest that CXCR4 signaling promotes PMT and shortens survival in GBM and highlights its inhibition as a potential therapeutic strategy.

The vascular endothelial cell-expressed prion protein doppel promotes angiogenesis and blood-brain barrier development.

The central nervous system (CNS) contains a complex network of blood vessels that promote normal tissue development and physiology. Abnormal control of blood vessel morphogenesis and maturation is linked to the pathogenesis of various neurodevelopmental diseases. The CNS-specific genes that regulate blood vessel morphogenesis in development and disease remain largely unknown. Here, we have characterized functions for the gene encoding prion protein 2 (Prnd) in CNS blood vessel development and physiology. Prnd encodes the glycosylphosphatidylinositol (GPI)-linked protein doppel, which is expressed on the surface of angiogenic vascular endothelial cells, but is absent in quiescent endothelial cells of the adult CNS. During CNS vascular development, doppel interacts with receptor tyrosine kinases and activates cytoplasmic signaling pathways involved in endothelial cell survival, metabolism and migration. Analysis of mice genetically null for Prnd revealed impaired CNS blood vessel morphogenesis and associated endothelial cell sprouting defects. Prnd-/- mice also displayed defects in endothelial barrier integrity. Collectively, these data reveal novel mechanisms underlying doppel control of angiogenesis in the developing CNS, and may provide new insights about dysfunctional pathways that cause vascular-related CNS disorders.

The Role of Hyperexcitability in Gliomagenesis.

Glioblastoma is the most common malignant primary brain tumor. Recent studies have demonstrated that excitatory or activity-dependent signaling-both synaptic and non-synaptic-contribute to the progression of glioblastoma. Glutamatergic receptors may be stimulated via neuron-tumor synapses or release of glutamate by the tumor itself. Ion currents generated by these receptors directly alter the structure of membrane adhesion molecules and cytoskeletal proteins to promote migratory behavior. Additionally, the hyperexcitable milieu surrounding glioma increases the rate at which tumor cells proliferate and drive recurrent disease. Inhibition of excitatory signaling has shown to effectively reduce its pro-migratory and -proliferative effects.

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors.

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.

Varied histomorphology and clinical outcomes of FGFR3-TACC3 fusion gliomas.

Targeted therapies for driver gene fusions in cancers have yielded substantial improvements in care. Here, the authors outline a case series of 6 patients with FGFR3-TACC3 fusion in primary brain tumors ranging from polymorphous low-grade neuroepithelial tumor of the young to papillary glioneuronal tumors and glioblastoma (GBM). Previous studies indicated the FGFR3-TACC3 fusion provides survival benefit to GBM patients. Consistent with this, 2 patients with GBM had unexpectedly good outcomes and survived for 5 and 7 years, respectively. In contrast, 2 patients with initially lower graded tumors survived only 3 years and 1 year, respectively. One patient received erdafitinib, a targeted FGFR inhibitor, for 3 months at late disease recurrence and no response was seen. There were varied histomorphological features, including many cases that lacked the characteristic FGFR3-TACC3 pathology. The findings of this cohort suggest that molecular testing is justified, even for glioma cases lacking classic histopathological signatures. Currently, FGFR3-TACC3 fusion gliomas are often classified on the basis of histopathological features. However, further research is needed to examine whether IDH1/2-wild-type tumors with FGFR3-TACC3 fusion should be classified as a subtype on the basis of this molecular fusion. Because patients with IDH1/2-wild-type GBM with FGFR3-TACC3 fusion have improved survival, routine molecular testing for this mutation in patients enrolled in clinical trials and subsequent stratification may be warranted.

Laser interstitial thermal therapy for newly diagnosed glioblastoma.

Gliomas are the most frequent primary brain tumor in adults. Patients with glioblastoma (GBM) tumors deemed inoperable with open surgical techniques and treated only with chemo/radiation have a median overall survival of less than 9 months. Laser interstitial thermal therapy (LITT) has emerged as a cytoreductive alternative to surgery for these patients. The present study describes the outcomes of twenty patients with newly diagnosed, IDH wild-type glioblastoma treated with LITT. We retrospectively reviewed patients with newly diagnosed, unresectable GBM who underwent LITT at our institution. Progression-free survival (PFS) was the primary endpoint measured in our study, defined as time from LITT to disease progression. Results Twenty patients were identified with newly diagnosed, inoperable GBM lesions who underwent LITT. The overall median PFS was 4 months (95% CI = 2 - N/A, upper limit not reached). The median progression-free survival (PFS) for patients with less than 1 cm 3 residual tumor (gross total ablation, GTA) was 7 months (95% CI = 6 - N/A, upper limit not reached), compared to 2 months (95% CI = 1 - upper limit not reached) for patients with a lower GTA (p = .0019). The median overall survival was 11 months (95% CI = 6 - upper limit not reached). Preoperative Karnofsky performance score (KPS) less than or equal to 80 and deep-seated tumor location were significantly associated with decreased PFS (HR, .18, p = .03; HR, .08, p = .03, respectively). At the end of 1 month, only 4 patients (20%) experienced persistent motor deficits. LITT is a safe and effective treatment for patients with unresectable, untreated GBM with rates of survival and local recurrence comparable to patients with surgically accessible lesions treated with conventional resection. Careful patient selection is needed to determine if GTA is attainable.

Single-center outcomes for percutaneous pedicle screw fixation in metastatic spinal lesions: can spontaneous facet fusion occur?

OBJECTIVE: Survival of cancer patients continues to improve with systemic treatment advancements, leading to an increase in cancer-related complications such as pathological spinal fractures. In this study, the authors aimed to evaluate the outcome of percutaneous stabilization with cement augmentation of the pedicle screws in the management of patients with metastatic cancer to the spine. METHODS: The authors reviewed a retrospective case series of 74 patients with symptomatic pathological spine fractures treated with cement-augmented pedicle screws implanted with a percutaneous technique. The mean imaging follow-up was 11.3 months. Data on demographics, clinical outcomes, and complications were collected. Cement extravasation, spinal hardware integrity, and fusion rates were assessed on CT scans. RESULTS: Among 50 patients with follow-up imaging, 23 patients (46%) showed facet joint fusion. The length of segmental stabilization was not a significant predictor of the occurrence of fusion. Pre- or postoperative radiation therapy, postoperative chemotherapy, and the location of spinal lesions did not have a statistically significant effect on the occurrence of fusion. Patients older than 60 years of age were more likely to have fusion across facet joints compared with younger patients. There was a significant difference in the mean visual analog scale pain score, with 6.28 preoperatively and 3.41 postoperatively, regardless of fusion status (p < 0.001). Cement extravasation was seen in 51% of the cohort, but in all instances, patients remained asymptomatic. Most importantly, the incidence of hardware failure was low (4%). CONCLUSIONS: Percutaneous fixation with cement-augmented pedicle screws in patients with pathological spine fractures provides an improvement in mechanical back pain, with a low incidence of failure, and in some patients, spontaneous facet fusion was observed. Further research is necessary with regard to both short-term benefits and long-term outcomes.

A Survey of Usage of Penile Prosthesis.

BACKGROUND: Implantation of an inflatable penile prosthesis (IPP) has high success and satisfaction rates, but there remains a paucity of evidence examining non-usage of IPP and reasons for discontinuation. AIM: To identify how frequent patients use their prosthesis and their personal reasons for no longer using it. METHODS: We conducted a survey of all patients who underwent an IPP implantation by a single surgeon over a 6-year period, between 2012 and 2018. After application of inclusion and exclusion criteria, a total of 114 patients formed the final cohort. Patients were initially surveyed via mail with a questionnaire; those who did not respond were surveyed via telephone. The factors determining patient selection for IPP implantation included suitability for general anesthesia, manual dexterity to use the device by the patient or their partner on a demonstration device, and presence of refractory erectile dysfunction, HbA1C lower than 8.5, or need for a revision of a previously placed IPP. Universally, a 3-piece AMS 700 Series implant was placed via the penoscrotal approach. Data were analyzed with Pearson chi square test, and survivability of the device was assessed with Kaplan-Meier survival curve. OUTCOMES: The main outcomes of this study are the frequency of IPP usage and reasons for discontinuation. RESULTS: The survey participation rate was 97%. The mean age of patient was 64 years (range 34-83 years), and the mean time between surgery and completion of survey was 2.98 years (range 0.25-7.4 years). Kaplan-Meier curve demonstrated that 68% of the patients were using the IPP at 5 years after implantation. Using the age 70 years as a cutoff, 18 (22%) patients younger than 70 years and 14 (42%) patients older than 70 years discontinued using the IPP (P = .029). The commonest reasons for discontinuation were poor health to engage in sexual activity (2.6%), loss of companion (19%), loss of interest in sex (2.6%), and device malfunction with no further interest in revision of prosthesis (14%). CLINICAL IMPLICATIONS: The clinical implication of this study was improved patient selection for device implantation. STRENGTHS AND LIMITATIONS: To our knowledge, no other study has investigated reasons for patients no longer using their prosthesis. Our study has several limitations including that it is a cross-sectional analysis, our survey is not validated, this is a single-surgeon experience, we have a small sample size, and we did not differentiate between virgin implant and reimplantation. CONCLUSION: Our study shows a high rate (28%) of non-usage of IPP, more so in men older than the age of 70 years in the first 5 years of implantation. Knoll P, Rai S, Talluri S, et al. A Survey of Usage of Penile Prosthesis. J Sex Med 2020;17:2287-2290.

Electrophysiological and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons.

Neuropathic pain encompasses a diverse array of clinical entities affecting 7-10% of the population, which is challenging to adequately treat. Several promising therapeutics derived from molecular discoveries in animal models of neuropathic pain have failed to translate following unsuccessful clinical trials suggesting the possibility of important cellular-level and molecular differences between animals and humans. Establishing the extent of potential differences between laboratory animals and humans, through direct study of human tissues and/or cells, is likely important in facilitating translation of preclinical discoveries to meaningful treatments. Patch-clamp electrophysiology and RNA-sequencing was performed on dorsal root ganglia taken from patients with variable presence of radicular/neuropathic pain. Findings establish that spontaneous action potential generation in dorsal root ganglion neurons is associated with radicular/neuropathic pain and radiographic nerve root compression. Transcriptome analysis suggests presence of sex-specific differences and reveals gene modules and signalling pathways in immune response and neuronal plasticity related to radicular/neuropathic pain that may suggest therapeutic avenues and that has the potential to predict neuropathic pain in future cohorts.

The use of laser interstitial thermal therapy in the treatment of brain metastases: a literature review.

PURPOSE: The aim of this paper is to discuss the current evidence for Laser Interstitial Thermal Therapy (LITT) in the treatment of brain metastases, our current recommendations for patient selection and the future perspectives for this therapy. We have also touched upon the possible complications and role of systemic therapy coupled with LITT for the treatment of brain metastases. MATERIAL AND METHODS: Two authors carried out the literature search using two databases independently, including PubMed, and Web of Science. The review included prospective and retrospective studies using LITT to treat brain metastases. RESULTS: Twenty-two original articles were analyzed in this review, particularly clinical outcomes and complications. We have also provided our institutional experience in the use of LITT to treat brain metastases and addressed future perspectives for the use of this technology. CONCLUSIONS: The current literature supports LITT as a safe and effective therapy for patients with brain metastases that have failed SRS. Larger studies are still required to better evaluate the use of systemic therapy in concomitance with LITT. New images modalities may enable optimized treatment and outcomes.

Virtual education in neurosurgery during the COVID-19 pandemic.

OBJECTIVE: Neurosurgical education in the US has changed significantly as a consequence of the novel coronavirus (COVID-19) pandemic. Institutional social distancing requirements have resulted in many neurosurgical programs utilizing video conferencing for educational activities. However, it is unclear how or if these practices should continue after the pandemic. The objective of this study was to characterize virtual education in neurosurgery and understand how it should be utilized after COVID-19. METHODS: A 24-question, 3-part online survey was administered anonymously to all 117 US neurosurgical residency programs from May 15, 2020, to June 15, 2020. Questions pertained to the current use of virtual conferencing, preferences over traditional conferences, and future inclinations. The Likert scale (1 = strongly disagree, 3 = neutral, 5 = strongly agree) was used. Comparisons were calculated using the Mann-Whitney U-test. Statistical significance was set at 0.05. RESULTS: One-hundred eight responses were recorded. Overall, 38 respondents (35.2%) were attendings and 70 (64.8%) were trainees. Forty-one respondents (38.0%) indicated attending 5-6 conferences per week and 70 (64.8%) attend national virtual conferences. When considering different conference types, there was no overall preference (scores < 3) for virtual conferences over traditional conferences. In regard to future use, respondents strongly agreed that they would continue the practice at some capacity after the pandemic (median score 5). Overall, respondents agreed that virtual conferences would partially replace traditional conferences (median score 4), whereas they strongly disagreed with the complete replacement of traditional conferences (median score 1). The most common choices for the partial replacement of tradition conferences were case conferences (59/108, 55%) and board preparation (64/108, 59%). Lastly, there was a significant difference in scores for continued use of virtual conferencing in those who attend nationally sponsored conferences (median score 5, n = 70) and those who do not (median score 4, n = 38; U = 1762.50, z = 2.97, r = 0.29, p = 0.003). CONCLUSIONS: Virtual conferences will likely remain an integral part of neurosurgical education after the COVID-19 pandemic has abated. Across the country, residents and faculty report a preference for continued use of virtual conferencing, especially virtual case conferences and board preparation. Some traditional conferences may even be replaced with virtual conferences, in particular those that are more didactic. Furthermore, nationally sponsored virtual conferences have a positive effect on the preferences for continued use of virtual conferences.

DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Nav1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Nav1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Nav1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Nav1.7 associated with spontaneous activity. Nav1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.SIGNIFICANCE STATEMENT This work demonstrates that the expression and function of the voltage-gated sodium channel Nav1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Nav1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Nav1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class.

Fractionated stereotactic radiotherapy for local control of resected brain metastases.

PURPOSE: Postoperative stereotactic radiosurgery (SRS) has been shown to establish local control in patients with resected brain metastases, yet its efficacy may be limited, particularly for resected lesions with large post-operative resection cavities. We describe the efficacy of postoperative fractionated stereotactic radiotherapy (FSRT) for local control in patients who have undergone resection for brain metastases. METHODS: In this retrospective cohort study, we analyzed patients who received FSRT for resected brain metastases in 3 or 5 fractions. Time to local recurrence was the primary endpoint in this study. RESULTS: Sixty-seven patients (n = 29 female, n = 38 male) met study criteria for review. The median age of the cohort was 62 years (range 18-79 years). Median preoperative tumor volume was 11.1 cm3 (range 0.4-77.0 cm3). The rate of local control was 91.0% at 6 months, 85.1% at 12 months, and 85.1% at 18 months. Estimates of freedom from local recurrence at 6 and 12 months were 90.9% and 84.3%, respectively. Higher biologically equivalent doses (BED10) were found to be predictive of longer freedom from local recurrence on univariate and multivariable analysis. Larger cavity volumes were found to correspond to longer time to local recurrence on univariate and multivariable analysis. CONCLUSION: Our results suggest that postoperative FSRT may be an effective method for providing local control to the surgical bed in patients with resected brain metastases, particularly for larger tumors not amenable to conventional, single-fraction SRS. Additional prospective studies are needed to confirm these findings.

Correction to: Volumetric response of progressing post-SRS lesions treated with laser interstitial thermal therapy.

The original article was published with an incorrect protocol number. The correct protocol number is DR07-0585.

The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.

Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.