NOTCH PATHWAY IN GSC

Role of Notch signaling pathway in Glioma Stem Cells

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 Obiettivo del progetto (Objective)

'Glioblastoma multiforme (GBM) is the most common malignant intracranial tumor in adults. Despite the knowledge of the genetic alterations associated to GBM and the improvement in neurosurgery and chemo- and radiotherapy, little improvement has been achieved in the median survival. Recently, glioma stem cells (GSCs) have been identified to be responsible of the origin, recurrence and drug resistance in GBM, constituing so an attractive therapeutic target in the fight against gliomas. The present project aims to study the biology of GSCs and characterize their genomic and transcriptomic in response to inhibitors of the Notch pathway. This pathway has been demonstrated to be very important in glioma and alterations in components of this pathway have been identified in GBM. The research line proposed here will be multidisciplinary and in close contact with the patient. The objectives of the present project are: 1. Isolation of GSC from clinical samples obtained after brain surgery through sorting for stem cell markers and characterization by SNP arrays, RT-PCR, CGH, etc. 2. Analysis of the response to Notch inhibitors in GSCs ex vivo and in vivo. Analysis of the status of this pathway in GSC and the response to Notch inhibitors in culture (proliferation, apoptosis, neurosphere formation, differentiation, etc) and in vivo after injection of GSCs intracranially into mice. Gene expression analysis of tumors treated with Notch inhibitors in order to identify genes associated with response to treatment. 3. Test of candidate genes involved in resistance to treatment in vitro and in vivo. By blockade using RNA interference or inhibitors. 4. Clinical correlation. Results obtained in the laboratory will be correlated with clinical data from patients involved in the Notch inhibitor clinical trial in our Hospital. Since this GSCs share characteristics with other cancer stem cells, such as colon and breast, the results of this study can be extrapolated to other tumor types.'

Introduzione (Teaser)

Cancer stem cells constitute a relatively new discovery with great clinical implications. Targeting this cell population may be all that is needed to eradicate the tumour.

Descrizione progetto (Article)

Glioblastoma multiforme (GBM) is the most common malignant intracranial tumour in adults. Significant progress has been made with respect to determining the associated genetic alterations and surgical treatment. However, this has translated into little improvement in patient median survival overall.

Emerging evidence indicates that a sub-population of cancer cells possess stem cell-like properties and could thus be responsible for tumour development, maintenance and drug resistance. Given the aggressive nature of GBM and the poor survival, novel treatment strategies are urgently required.

Scientists on the EU-funded NOTCH PATHWAY IN GSC (Role of Notch signaling pathway in glioma stem cells) project proposed to investigate the role of the Notch signalling pathway in GBM. Notch signalling is known to be involved in normal neural stem cells and an overactive pathway has been linked with GBM. It therefore represents a putative therapeutic target against GBM.

In this context, the consortium isolated stem cells from patients with GBM to find a highly active Notch signalling pathway. They discovered that Notch signalling was partly induced by TGF?, a molecule implicated in the maintenance of GBM stem cells.

Scientists activated the Notch pathway in patient-derived cultures and discovered that it upregulated stem cell markers such as CD44. A decrease in GBM stem cells was seen upon Notch inhibition with a ?-secretase inhibitor, clearly underscoring the involvement of Notch in cell survival. The reduction in stem cells was even more pronounced when a combination of Notch and TGF? receptor inhibitors were used at the same time.

Taken together, the results of the NOTCH PATHWAY IN GSC study demonstrate the interplay between Notch and TGF? signalling in the maintenance of GBM stem cells. The consortium is confident that a combinatorial targeting of these two pathways will be more therapeutically beneficial than either of these treatments used alone.