DCXGLIOMA

Dissemination of proneural brain cancer cells: implication of partial and reversible differentiation into Dcx+ cells

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 Obiettivo del progetto (Objective)

'Gliomas describe a range of devastating and progressive brain tumours affecting around 25000 people each year in Europe. Glioblastomas represent the most severe and frequent form of gliomas. A major finding in the field of glioblastomas is the recent identification of cancer stem cells within the tumour, holding a high tumorigenic potential. Those stem cell-like cancer cells are multipotent and resistant to radio- and chemotherapy, and are thus very likely to be responsible for the tumour recurrence after surgical resection. They possess as well high migratory properties, strongly understudied so far. Their anarchic dispersion through the parenchyma of patients represents the main hurdle to surgical resection therapy, and their ability to re-generate a tumour threatens the therapeutic outcome. That is why a deep understanding of the mechanisms preferentially borrowed by glioma stem cells to spread and survive should lead to adapted therapeutic strategies. This project is based on the original discovery by JP Hugnot’s group that glioma cells can spontaneously express the neuroblast marker Dcx to enter a migratory program in vitro, and in vivo. Interestingly, Dcx and Dcx- glioma cells from the same culture share different migratory and tumorigenic properties. This project aims at deciphering the respective intrinsic properties of Dcx and Dcx- gliomas cells in terms of migration and tumorigenicity, and to identify which molecular pathways influence these properties (with a focus on Notch and Shh based on preliminary data). For that, several resources are already available and in Pr Hugnot’s group: cell sorting, gliomas cell lines reportering the expression of Dcx (Gli4 pDcx-GFP), migration assays, cell transplantation of Dcx or Dcx- cells in the brain of nude mice. When further developed, these results will provide a substantial advance in the field of brain cancer research, and will open up significant therapeutic perspectives for the treatment of gliomas.'

Introduzione (Teaser)

Most brain tumours have devastating outcomes, sometimes within just months after diagnosis. Targeting cancer stem cells is emerging as an effective approach to tumour eradication.

Descrizione progetto (Article)

Glioblastomas are a group of highly invasive and aggressive brain tumours. Their heterogeneous nature makes them difficult to discriminate from normal tissue hampering the effective treatment of this incurable pathology. Recently, a sub-population of cancer stem cells has been identified to which scientists attribute tumour recurrence after surgery.

Glioblastoma stem cells have a high tumorigenic potential and exhibit resistance to radiotherapy and chemotherapy. Their migratory properties and sporadic dispersion through the parenchyma represent major hurdles to targeted therapy.

With this in mind, the EU-funded DCXGLIOMA project set out to understand the mechanisms underlying glioblastoma stem cell properties. Work was based on the discovery that glioma cells can spontaneously express the neuroblast marker Dcx and acquire different migratory and tumorigenic properties.

To study the molecular and cellular properties of Dcx positive and negative cells, researchers isolated glioblastoma stem cells from patients and generated spheres in culture. In normal cells, Dcx is associated with a migrating cell phenotype and is expressed in neuronal cells. In tumour cells, Dcx expression correlates with lower proliferation and clonogenicity.

Regulation of Dcx in glioblastoma stem cells was mediated by various molecular pathways such as SHH and Notch and by post-transcriptional mechanisms. This indicated that in glioblastoma, Dcx positive cells seem to be a less aggressive form of cancerous cells. This is supported by evidence from other glioblastoma studies that link Dcx with better prognosis.

Based on the findings, DCXGLIOMA scientists propose that manipulation of Dcx expression in glioblastoma cells could be exploited for slowing down the progression of this fatal disease. Given the capacity of cancer stem cells to regenerate a tumour and threaten the therapeutic outcome, adapting treatment strategies to eliminate cancer stem cells seems to be the way forward.