Purpose: Glioblastoma (GBM) is the most common primary brain tumor. The identification of blood biomarkers reflecting the tumor status represents a major unmet need for optimal clinical management of patients with GBM. Their high number in body fluids, their stability, and the presence of many tumor-associated proteins and RNAs make extracellular vesicles potentially optimal biomarkers. Here, we investigated the potential role of plasma extracellular vesicles from patients with GBM for diagnosis and follow-up after treatment and as a prognostic tool. Experimental Design: Plasma from healthy controls (n ¼ 33), patients with GBM (n ¼ 43), and patients with different central nervous system malignancies (n ¼ 25) were collected. Extracellular vesicles were isolated by ultracentrifugation and characterized in terms of morphology by transmission electron microscopy, concentration, and size by nanoparticle tracking analysis, and protein composition by mass spectrometry. An orthotopic mouse model of human GBM confirmed human plasma extracellular vesicle quantifications. Associations between plasma extracellular vesicle concentration and clinicopathologic features of patients with GBM were analyzed. All statistical tests were two-sided. Results: GBM releases heterogeneous extracellular vesicles detectable in plasma. Plasma extracellular vesicle concentration was higher in GBM compared with healthy controls (P < 0.001), brain metastases (P < 0.001), and extra-axial brain tumors (P < 0.001). After surgery, a significant drop in plasma extracellular vesicle concentration was measured (P < 0.001). Plasma extracellular vesicle concentration was also increased in GBM-bearing mice (P < 0.001). Proteomic profiling revealed a GBM-distinctive signature. Conclusions: Higher extracellular vesicle plasma levels may assist in GBM clinical diagnosis: their reduction after GBM resection, their rise at recurrence, and their protein cargo might provide indications about tumor, therapy response, and monitoring.

Glioblastoma (GBM) represents the most aggressive and lethal disease of the central nervous system. Diagnosis is delayed following the occurrence of symptoms, and treatment is based on standardized approaches that are unable to cope with its heterogeneity, mutability, and invasiveness. The follow-up of patients relies on burdensome schedules for magnetic resonance imaging (MRI). However, to personalize treatment, biomarkers and liquid biopsy still represent unmet clinical needs. Extracellular vesicles (EVs) may be the key to revolutionize the entire process of care for patients with GBM. EVs can be collected noninvasively (e.g., blood) and impressively possess multilayered information, which is constituted by their concentration and molecular cargo. EV-based liquid biopsy may facilitate GBM diagnosis and enable the implementation of personalized treatment, resulting in customized care for each patient and for each analyzed time point of the disease, thereby tackling the distinctive heterogeneity and mutability of GBM that confounds effective treatment. Herein, we discuss the limitations of current GBM treatment options and the rationale behind the need for personalized care. We also review the evidence supporting GBM-associated EVs as a promising tool capable of fulfilling the still unmet clinical need for effective and timely personalized care of patients with GBM.

Inhibiting LSD1 reduces glioblastoma tumor-initiating cell survival by impeding their ability to handle the stress through the deregulation of ATF4.

Enhanced fatty acid synthesis is a hallmark of tumors, including glioblastoma. SREBF1/2 regulates the expression of enzymes involved in fatty acid and cholesterol synthesis. Yet, little is known about the precise mechanism regulating SREBP gene expression in glioblastoma. Here, we show that a novel interaction between the coactivator/co-repressor CTBP2 and the tumor suppressor ZBTB18 regulates the expression of SREBP genes. Our study points at CTBP2 as a co-activator of SREBP genes whose complex activity is impaired by ZBTB18. ZBTB18 binding to the SREBP gene promoters is associated with reduced LSD1 activity leading to increased dimethylation of lysine 9 (H3K9me2), and concomitant decrease of H3K4me3 with consequent repression of the SREBP genes. In line with our findings, lipidomics analysis shows a reduction of several phospholipid species upon ZBTB18 expression. Our results thus outline a new epigenetic mechanism enrolled by ZBTB18 and its cofactors to regulate fatty acid synthesis which could be targeted to treat glioblastoma patients. STATEMENT OF SIGNIFICANCEDe novo lipogenesis is a hallmark of many cancers, including glioblastoma; therefore, revealing how fatty acid synthesis enzymes are regulated may open up new venues in therapy. Moreover, understanding how epigenetic control of key cancer genes occurs may contribute to shed light on common regulatory mechanisms shared by other tumor suppressors in different cancers.