The Rho-GTPase Cdc42 is a key regulator of the actin and microtubule network, thereby regulating cellular processes like cell polarization and motility or membrane traffic. Two isoforms of Cdc42 exist; one ubiquitously expressed, the other being brain-specific. Most studies have focused on the former and specific functions of the brain-restricted variant remain obscure. Recent observations from Etienne-Manneville’s lab uncover an isoform-specific alteration of Cdc42 expression in glioblastoma, a most invasive type of brain tumour, leading us to investigate the individual functions of each variant. In this project, we will compare the intracellular localization patterns of the two isoforms and investigate the underlying targeting mechanisms. The individual subset of binding partners will be analyzed, as well as how alterations of Cdc42 variants expression may affect membrane protrusion, polarization and motility in normal astrocytes. Results will then be compared to that of reconstituted or RNAi-treated glioblastoma cells, in order to define the consequences of abnormal expression of Cdc42 isoforms in the invasiveness of brain tumour cells. Furthermore, variants of the polarity proteins aPKC and Par6, which were also found to be misregulated in glioblastoma, will be analysed for their individual relevance in the context of migration and polarity. Understanding the regulatory background leading to the high invasiveness of glioblastoma is most important, as single tumour cells commonly infiltrate brain tissue several centimetres away from the main tumour, making a complete surgical clearance impossible. Characterizing “risk factors” in glioblastoma progression, as potentially given by misregulated expression of proteins influencing cell migration and polarity, may furthermore allow predicting more precisely the development of brain tumours and may provide the basis for novel therapies aimed at blocking tumour cell infiltration as a complement to surgical interventions.
Fields of science
Call for proposal
See other projects for this call