Human glioblastoma arises from subventricular zone cells with low-level driver mutations

Lee, Joo Ho; Lee, Jeong Eun; Kahng, Jee Ye; Kim, Se Hoon; Park, Joon Seong; Yoon, Seon‐Jin; Um, Ji Yong; Kim, Woo Kyeong; Lee, Jake June-Koo; Park, Junseong; Kim, Eui Hyun; Lee, Ji Hyun; Lee, Joon Hyuk; Chung, Won‐Suk; Ju, Young Seok; Park, Sung-Hong; Chang, Jong Hee; Kang, Seok‐Gu; Lee, Jehee

doi:10.1038/s41586-018-0389-3

Cited by 513 publications

(495 citation statements)

References 49 publications

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“…It is widely accepted that GBM originate from the stem cell reservoirs responsible for adult neurogenesis in the brain (Singh et al, 2004;Zhu et al, 2005;Siebzehnrubl et al, 2011;Westphal and Lamszus, 2011). There are several reports that support that neural stem cells localized at the subventricular zone (SVZ) are the origin of glioblastoma (Lee et al, 2018;Gimple et al, 2019). Neural stem cell fate is controlled by environmental cues, among which cytokines play a crucial role (Ming and Song, 2011).…”

Section: Introductionmentioning

confidence: 99%

NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells

García-Gómez

Dadras²,

Bellomo³

et al. 2019

Preprint

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Glioblastoma (GBM) is the most aggressive and common glioma subtype with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy, thus more effective approaches are needed. The glioblastoma tumoral mass is characterized by a small cellular subpopulation, the Glioblastoma stem cells (GSCs), which has been held accountant for initiation, invasion, proliferation, relapse and resistance to chemo-and radiotherapy. Targeted therapies against GSCs are crucial, and so is the understanding of the molecular mechanisms that govern the GSCs.Transforming growth factor β (TGFβ), platelet growth factor (PDGF) signalling and Reactive Oxygen Species (ROS) production govern and regulate cancer-stem cell biology. In this work, we focus on the role of the NADPH oxidase 4 (NOX4) downstream of TGFβ signalling in the GSCs. NOX4 utilises NADPH to generate ROS; TGFβ induces NOX4 expression, thus increasing ROS production.Interestingly, NOX4 itself regulates GSC self-renewal and modulates Since TGFβ regulates PDGFB in GSC, we analysed how PDGFB modulates NOX4 expression and increases ROS production. Both TGFβ and PDGF signalling regulate GSC proliferation in a NOX4/ROS-dependent manner. The transcription factor NRF2, involved in the transcriptional regulation of antioxidant and metabolic responses, is regulated by both TGFβ and NOX4. This results in an antioxidant response, which positively contributes to GSC self-renewal and proliferation. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.

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Section: Introductionmentioning

confidence: 99%

NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells

García-Gómez

Dadras²,

Bellomo³

et al. 2019

Preprint

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“…4 In the world each year, there are 100 000 new cases of glioblastoma. 6 The histological grading of gliomas is categorised according to World Health Organization (WHO) guidelines. Strikingly, the 5year relative survival (just 4.6% at 5 years) for glioblastoma patients has remained stable over the last three decades.…”

Section: Glioblastoma: the Details Incidence Pathology And Classificmentioning

confidence: 99%

“…However, recent evidence indicates that glioblastoma arises instead from neural stem cells within the subventricular zone of the brain. 6 The histological grading of gliomas is categorised according to World Health Organization (WHO) guidelines. The highest grade (grade IV) of glioma is glioblastoma, and the diagnosis depends on observations of high cellularity, atypical glial cells, and microvascular proliferation (MVP), or significant necrosis or both.…”

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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“…In the brain, glial cells are immersed in an electric field created by tissue polarity from brain macrostructures as well as the local field potentials which are established from the action potentials fired by the neurons 12 . A weak endogenous electric current has been shown to serve as a guidance cue for neuroblast migration from the subventricular zone in mouse 13 , a region speculated as the origin of glioma tumorigenesis 14 . Thus, the physiological a) amy.shen@oist.jp electric fields in the brain may play an important role in mediating the glioma tumorigenesis and invasion [15][16][17][18][19] .…”

Section: Introductionmentioning

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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Human glioblastoma arises from subventricular zone cells with low-level driver mutations

Cited by 513 publications

References 49 publications

NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells

NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells

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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