Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed ...that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Studies showed that a bulky glycocalyx potentiates integrin mechanosignalling and tissue tension and promotes a mesenchymal, stem-like phenotype in GBMs. Gain- and loss-of-function studies implicated integrin mechanosignalling as an inducer of GBM growth, survival, invasion and treatment resistance, and a mesenchymal, stem-like phenotype. Mesenchymal-like GBMs were highly contractile and expressed elevated levels of glycoproteins that expanded their glycocalyx, and they were surrounded by a stiff extracellular matrix that potentiated integrin mechanosignalling. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignalling and a bulky glycocalyx, implying a causal link towards a mesenchymal, stem-like phenotype in GBMs. Strategies to ameliorate GBM tissue tension offer a therapeutic approach to reduce mortality due to GBM.
Glioblastoma (GBM) is known as a tumor type, which arises from astrocytes. Several studies indicated that GBM tumor cells are malignant. This is because of the fact that they consist of different ...cell types, which are reproducing very quickly and are also supported by a large network of blood vessels. The correct identification of various stages of GBM could help to better treat the patients with this disease. Therefore, new biomarkers such as exosomes and microRNAs (miRNAs) may help us to learn more about GBM and they may also lead to a more effective treatment for patients with GBM. Exosomes have emerged as biological vehicles, which can perform various tasks in carcinogenesis pathways such as PI3K/AKT, SOX2, PTEN, ERK, and STAT3. The miRNAs are known as small noncoding RNAs that are involved in several GBM pathogenic events. These molecules have key roles in various biological processes such as angiogenesis, metastasis and tumor growth. In this study, we highlighted various exosomes and miRNAs that could be used for diagnosis and/or prognosis biomarkers in patients with GBM.
Glioblastoma is a universally lethal cancer with a median survival time of approximately 15 months. Despite substantial efforts to define druggable targets, there are no therapeutic options that ...notably extend the lifespan of patients with glioblastoma. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology for use in orthotopic patient-derived xenograft models, creating a high-throughput negative-selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators needed for cell survival in vivo are non-overlapping with those required in vitro. We identified transcription pause-release and elongation factors as one set of in vivo-specific cancer dependencies, and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivo stress and stimulus response pathways through enhancer-mediated transcriptional pause-release, promoting cell survival specifically in vivo. Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, suggesting that targeting transcription elongation machinery may be an effective therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of 'cancer dependencies' not identified by previous in vitro approaches, and could supply new opportunities for therapeutic intervention.
Accumulating evidence demonstrates the oncogenic roles of lncRNA (long non-coding RNA) molecules in a wide variety of cancer types including glioma. Equally important, However, tumorigenic functions ...of lncRNA in glioma remain largely unclear. A recent study suggested lncRNA SNHG15 played a role for regulating angiogenesis in glioma but its role in the tumor microenvironment (TME) was not investigated.
First, we showed that SNHG15 was upregulated in GBM cells and associated with a poor prognosis for the patients of GBM using public databases. Next, we collected temozolomide sensitive (TMZ-S) and resistant (TMZ-R) clinical samples and demonstrated that co-culturing TMZ-R cells with HMC3 (microglial) cells promoted M2-polarization of HMC3 and the secretion of pro-GBM cytokines TGF-β and IL-6.
Comparative qPCR analysis of TMZ-S and TMZ-R cells showed that a significantly higher level of SNHG15, coincidental with a higher level of Sox2, β-catenin, EGFR, and CDK6 in TMZ-R cells. Subsequently, using bioinformatics tool, a potential mechanistic route for SNHG15 to promote GBM tumorigenesis was by inhibiting tumor suppressor, miR-627-5p which leads to activation of CDK6. Gene-silencing technique was employed to demonstrate that suppression of SNHG15 indeed led to the suppression of GBM tumorigenesis, accompanied by an increase miR-627-5p and decreased its two oncogenic targets, CDK6 and SOX-2. In addition, SNHG15-silenced TMZ-R cells became significantly sensitive towards TMZ treatment and less capable of promoting M2-phenotype in the HMC3 microglial cells. We then evaluated the potential anti-GBM activity of CDK6 inhibitor, palbociclib, using TMZ-R PDX mouse models. Palbociclib treatment significantly reduced tumorigenesis in TMZ-R/HMC3 bearing mice and SNHG15 and CDK6 expression was significantly reduced while miR-627-5p level was increased. Additionally, palbociclib treatment appeared to overcome TMZ resistance as well as reduced M2 markers in HMC3 cells.
Together, we provided evidence supporting the usage of CDK6 inhibitor for TMZ-resistant GBM cases. Further investigation is warranted for the consideration of clinical trials.
Abstract
Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding ...the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.
Glioblastoma is the most common and lethal primary malignant brain tumor in adults. Patients die from recurrent tumors that have become resistant to therapy. New strategies are needed to design ...future therapies that target resistant cells. Recent genomic studies have unveiled the complexity of tumor heterogeneity in glioblastoma and provide new insights into the genomic landscape of tumor cells that survive and initiate tumor recurrence. Resistant cells also co-opt developmental pathways and display stem-like properties; hence we propose to name them recurrence-initiating stem-like cancer (RISC) cells. Genetic alterations and genomic reprogramming underlie the innate and adaptive resistance of RISC cells, and both need to be targeted to prevent glioblastoma recurrence.
We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, ...mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.
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•GBM-intrinsic transcriptional subtypes: proneural, classical, mesenchymal•NF1 deficiency drives recruitment of tumor-associated macrophages/microglia•Resistance to radiotherapy may associate with M2 macrophage presence•CD8+ T cells are enriched in temozolomide-induced hypermutated GBMs at recurrence
Wang et al. define three IDH wild-type glioblastoma-intrinsic gene expression subtypes, which are partly shaped by the tumor immune environment. NF1 deficiency results in increased macrophage/microglia infiltration. Comparison of matched primary and recurrent tumors reveals frequent expression subtype changes.
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, with an incidence of 3.19 cases per 100,000 person years and remarkably poor prognosis showing a 5-year survival rate ...of 4-5%, and only a 26-33% survival rate at 2 years in clinical trials.
In this paper, we review the different types of treatment modalities based on the relevant databases. Methods of diagnosis will be described briefly.
Systemic compilation of the relevant literature.
Today's treatments cannot cure GBM patients but only extend their overall survival. The use of chemoradiation, immunotherapy, and radio sensitizers as an adjuvant therapy cannot reduce the high rates of recurrence within a few months after treatment. Radiotherapy will remain the backbone of the treatment but new treatment modalities must be developed.
Glioblastoma (GBM) is a lethal tumor that displays remarkable genetic heterogeneity. It is also known that GBM contains a cell hierarchy driven by GBM stem‐like cells (GSCs), responsible for tumor ...generation, therapeutic resistance, and relapse. An important and still open issue is whether phylogenetically related GSCs can be found in matched primary and recurrent GBMs, and reflect tumor genetic evolution under therapeutic pressure. To address this, we analyzed the mutational profile of GSCs isolated from either human primary GBMs (primary GSCs) or their matched tumors recurring after surgery and chemoradiotherapy (recurrent GSCs). We found that recurrent GSCs can accumulate temozolomide‐related mutations over primary GSCs, following both linear and branched patterns. In the latter case, primary and recurrent GSCs share a common set of lesions, but also harbor distinctive mutations indicating that primary and recurrent GSCs derive from a putative common ancestor GSC by divergent genetic evolution. Interestingly, TP53 mutations distinctive of recurrent GSCs were detectable at low frequency in the corresponding primary tumors and likely marked pre‐existent subclones that evolved under therapeutic pressure and expanded in the relapsing tumor. Consistently, recurrent GSCs displayed in vitro greater therapeutic resistance than primary GSCs. Overall, these data indicate that (a) phylogenetically related GSCs are found in matched primary and recurrent GBMs and (b) recurrent GSCs likely pre‐exist in the untreated primary tumor and are both mutagenized and positively selected by chemoradiotherapy. Stem Cells 2017;35:2218–2228
By comparing the mutational profile of matched neurospheres (cultures enriched in stem‐like cells, glioblastoma GBM stem‐like cells GSCs) derived from primary or recurrent GBM, genetic evolution can be observed. Recurrent GSCs are phylogenetically related with primary GSCs and can accumulate mutations following linear or divergent pathways, mirroring genetic evolution in the original tumor subclones. The subclones giving rise to recurrent tumors pre‐exist in the primary tumor, are selected by therapeutic pressure, and can concomitantly accumulate further genetic alterations for the mutagenic effect of chemoradiotherapy. Increased color saturation indicates increased mutational load. Dotted lines: presumptive ancestral tumor subclones inferred by the study of TP53 mutations in GSCs.
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