Glioblastoma heterogeneity and the tumour microenvironment: implications for preclinical research and development of new treatments

Perrin, Sally L.; Samuel, Michael S.; Koszyca, Barbara; Brown, Michael P.; Ebert, Lisa M.; Oksdath, Mariana; Gómez, Guillermo A.

doi:10.1042/bst20180444

Cited by 128 publications

(101 citation statements)

References 117 publications

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“…Despite aggressive interventions, the disease almost inevitably turns into recurrent GBM, for which no standard and effective treatment approach has been shown to prolong patient survival significantly . The overall survival of recurrent GBM is generally no more than half a year . Consequently, incurable GBM exerts challenging pressure on future work related to searching for novel treatment targets.…”

Section: Introductionmentioning

confidence: 99%

Role of alternative splicing signatures in the prognosis of glioblastoma

Xie

Dang

et al. 2019

Cancer Medicine

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Background Increasing evidence has validated the crucial role of alternative splicing (AS) in tumors. However, comprehensive investigations on the entirety of AS and their clinical value in glioblastoma (GBM) are lacking. Methods The AS profiles and clinical survival data related to GBM were obtained from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses were performed to identify survival‐associated AS events. A risk score was calculated, and prognostic signatures were constructed using seven different types of independent prognostic AS events, respectively. The Kaplan‐Meier estimator was used to display the survival of GBM patients. The receiver operating characteristic curve was applied to compare the predictive efficacy of each prognostic signature. Enrichment analysis and protein interactive networks were conducted using the gene symbols of the AS events to investigate important processes in GBM. A splicing network between splicing factors and AS events was constructed to display the potential regulatory mechanism in GBM. Results A total of 2355 survival‐associated AS events were identified. The splicing prognostic model revealed that patients in the high‐risk group have worse survival rates than those in the low‐risk group. The predictive efficacy of each prognostic model showed satisfactory performance; among these, the Alternate Terminator (AT) model showed the best performance at an area under the curve (AUC) of 0.906. Enrichment analysis uncovered that autophagy was the most enriched process of prognostic AS gene symbols in GBM. The protein network revealed that UBC, VHL, KCTD7, FBXL19, RNF7, and UBE2N were the core genes in GBM. The splicing network showed complex regulatory correlations, among which ELAVL2 and SYNE1_AT_78181 were the most correlated (r = −.506). Conclusions Applying the prognostic signatures constructed by independent AS events shows promise for predicting the survival of GBM patients. A splicing regulatory network might be the potential splicing mechanism in GBM.

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Section: Introductionmentioning

confidence: 99%

Role of alternative splicing signatures in the prognosis of glioblastoma

Xie

Dang

et al. 2019

Cancer Medicine

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“…Strikingly, the 5year relative survival (just 4.6% at 5 years) for glioblastoma patients has remained stable over the last three decades. 8 Although the molecular classification of glioblastoma informs prognosis, it has not yet provided definitive evidence to influence the use of immunotherapy. However, recent evidence indicates that glioblastoma arises instead from neural stem cells within the subventricular zone of the brain.…”

Section: Glioblastoma: the Details Incidence Pathology And Classificmentioning

confidence: 99%

“…Indeed, glioblastoma was historically known as glioblastoma multiforme in recognition of its particularly high inter-and intra-tumoral histological heterogeneity. 8 Although the molecular classification of glioblastoma informs prognosis, it has not yet provided definitive evidence to influence the use of immunotherapy. Finally, surprisingly for an aggressive cancer, glioblastoma does not metastasise outside of the CNS.…”

Section: Glioblastoma: the Details Incidence Pathology And Classificmentioning

confidence: 99%

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

2019

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Chimeric antigen receptor (CAR)‐T cell therapy is now approved in the United States and Europe as a standard treatment for relapsed/refractory B‐cell malignancies. It has also been approved recently by the Therapeutic Goods Administration in Australia and may soon be publicly reimbursed. This advance has accentuated scientific, clinical and commercial interest in adapting this exciting technology for the treatment of solid cancers where it is widely recognised that the challenges of overcoming a hostile tumor microenvironment are most acute. Indeed, CAR‐T cell technology may be of the greatest value for those cancers that lack pre‐existing immunity because they are immunologically ‘cold’, or have a low somatic tumor mutation load, or both. These cancers are generally not amenable to therapeutic immune checkpoint blockade, but CAR‐T cell therapy may be effective because it provides an abundant supply of autologous tumor‐specific T cells. This is achieved by using genetic engineering to re‐direct autologous T‐cell cytotoxicity towards a tumor‐associated antigen, bypassing endogenous T‐cell requirements for antigen processing, MHC‐dependent antigen presentation and co‐stimulation. One of the most challenging solid cancers is glioblastoma, which has among the least permissive immunological milieu of any cancer, and which is almost always fatal. Here, we argue that CAR‐T cell technology may counter some glioblastoma defences and provide a beachhead for furthering our eventual therapeutic aims of restoring effective antitumor immunity. Although clinical investigation of CAR‐T cell therapy for glioblastoma is at an early stage, we discuss three recently published studies, which feature significant differences in target antigen, CAR‐T cell phenotype, route of administration and tumor response. We discuss the lessons, which may be learned from these studies and which may guide further progress in the field.

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“…Similar results are reported in the electrotaxis of glioblastoma cells and spheroids 15,16,19,39 and lung adenocarcinoma 51 , showing that although molecular and surface marker makeups of the cell lines are similar, their electrotaxis responses can be completely different. The opposite electrotaxis results may reflect the fundamental heterogeneity among glioblastoma cells which has been speculated to contribute to the recurrence and therapeutic resistance after anti-tumor therapy [52][53][54][55][56] . Further elucidation of the correlation among electrotactic responses, metastatic properties of glioblastoma, and in situ electric field around the lesion may be beneficial to evaluate electrotaxis response as a predictive tool for glioblastoma metastasis.…”

Section: Electrotaxis Behavior May Reflect the Heterogeneity Of Glmentioning

confidence: 99%

Voltage-gated ion channels mediate the electrotaxis of glioblastoma cells in a hybrid PMMA/PDMS microdevice

Tsai

IJspeert

Shen

2020

Preprint

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Transformed astrocytes in the most aggressive form cause glioblastoma, the most common cancer in central nervous system with high mortality. The physiological electric field by neuronal local field potentials and tissue polarity may guide the infiltration of glioblastoma cells through the electrotaxis process. However, microenvironments with multiplex gradients are difficult to create. In this work, we have developed a hybrid microfluidic platform to study glioblastoma electrotaxis in controlled microenvironments with high throughput quantitative analysis by a machine learning-powered single cell tracking software. By equalizing the hydrostatic pressure difference between inlets and outlets of the microchannel, uniform single cells can be seeded reliably inside the microdevice. The electrotaxis of two glioblastoma models, T98G and U-251MG, require optimal laminin-containing extracellular matrix and exhibits opposite directional and electro-alignment tendencies. Calcium signaling is a key contributor in glioblastoma pathophysiology but its role in glioblastoma electrotaxis is still an open question. Anodal T98G electrotaxis and cathodal U-251MG electrotaxis require the presence of extracellular calcium cations. U-251MG electrotaxis is dependent on the P/Q-type voltage-gated calcium channel (VGCC) and T98G is dependent on the R-type VGCC. U-251MG and T98G electrotaxis are also mediated by A-type (rapidly inactivating) voltage-gated potassium channels and acidsensing sodium channels. The involvement of multiple ion channels suggests that the glioblastoma electrotaxis is complex and patient-specific ion channel expression can be critical to develop personalized therapeutics to fight against cancer metastasis. The hybrid microfluidic design and machine learning-powered single cell analysis provide a simple and flexible platform for quantitative investigation of complicated biological systems.

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Glioblastoma heterogeneity and the tumour microenvironment: implications for preclinical research and development of new treatments

Cited by 128 publications

References 117 publications

Role of alternative splicing signatures in the prognosis of glioblastoma

Role of alternative splicing signatures in the prognosis of glioblastoma

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

Voltage-gated ion channels mediate the electrotaxis of glioblastoma cells in a hybrid PMMA/PDMS microdevice

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