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

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

Glioblastomas are the most common and most devastating brain tumours, death generally occurring within a few months after diagnosis. Despite intensive efforts to target and destroy the cancerous cells, there is to date no efficient treatment against this deadly pathology. The heterogeneous and highly invasive properties of glioblastoma cells make them difficult to isolate and to discriminate from the non-cancerous cells present within the same brain region. Characterisation of the different cell subtypes forming the tumour is thus a necessary step towards targeted therapy. Our team is exclusively dedicated to the study of gliomas, and more specifically glioblastomas and low grade gliomas. This latter subtype of gliomas represents a less aggressive form of tumours, but ultimately degenerates into a high grade glioblastoma. Our laboratory works in close collaboration with the neurosurgery unit present in the same campus and generates glioblastoma cancer stem cell lines (gliospheres) isolated from the tumours of patients after surgery. One of our aims is to characterise at the cellular and molecular levels the different subtypes forming the tumour. We recently described, within the pool of glioblastoma stem cells, a subpopulation of cells expressing the neuroblast marker Doublecortin (Dcx). In the non-pathological context, Dcx is associated with a migrating cell phenotype and is expressed in cells engaged into neuronal differentiation. The aim of our two years project was to provide a full characterisation of the cellular and molecular properties of this particular Dcx+ cell subtype. We thus demonstrated that Dcx+ cells represent a specific cell type with distinct properties from the Dcx- cells present in the same culture. Notably, Dcx+ cells are less proliferative and less clonogenic than Dcx- glioblastoma stem cells. We identified as well two molecular markers (Hes5 and Gli1) able to trigger the expression of Dcx in glioblastoma stem cells. Additionnally, post-transcriptionnal mechanisms seem to be strongly involved in the regulation of Dcx expression, as indicated by the discrepancy between mRNA and protein levels of Dcx upon differentiation of the cells. On the basis of these findings, Dcx+ cells seem to be a less aggressive form of cancerous cells. Our project has highlighted a subpopulation of glioblastoma with less aggressive features than the other cells present in the same culture. This finding is in correlation with the fact that Dcx expression seems to be associated to a better prognostic as illustrated by the Caplan-Meier curves provided by the Rembrandt consortium. Being able to manipulate the expression of Dcx into glioblastoma cells in the brain of patients would thus be a critical advance in the aim to slow down the progression of this fatal disease.

Data: CORDIS, © European Union