Research project # Biophysical approach of the interaction between tau, microtubule and actin in cancer cell – an issue in the fight against the progression of glioblastoma
Despite recent advances, the number of patients with glioblastoma (GBM) is increasing and the main reason for treatment failures remains the ineffectiveness of conventional treatments for other cancers. Moreover, the dysfunction of cell migration in GBM is a proven factor of the disease. This process involves strong cell shape modifications and thus heavily relies on the redistribution and cooperation of cytoskeletal filamentous proteins, notably actin filaments and microtubules (MT). While the requirement of a crosstalk between MTs and actin is not questioned, mechanisms underlying the MT-actin organization by cross-linkers remain largely unexplored. In particular, little is known about the functional contribution of microtubule-associated proteins (MAPs) such as Tau known as a prominent stabilizer of MTs and promoting in vitro co-organization of MT and actin networks. Thus, a complete understanding of how cytoskeletal filaments contribute to biological functions in cell migration and more generally cell shape changes requires a deeper knowledge of how Tau governs cross-talk of MT and actin cytoskeletons. This project aims at deciphering the role of Tau in cell migration and the progression of GBM. Our hypothesis of work is that by interacting with both MTs and actin cytoskeletons, Tau could assist in addressing the (+) end of MTs to focal contacts (a phenomenon called ‘targeting’) necessary to cell adhesion to extracellular matrix. We propose (1) to characterize the interaction of Tau with both MTs and actin filaments directly in the cell; (2) to explore the interaction-activity relationship of Tau on major signaling pathways involved in cell migration, such as the Rho GTP-ase proteins (Rho, Rac, Cdc42); (3) to determine the impact of phosphorylation of Tau on three residues candidate as prognostic markers of GBM; and (4) to determine the impact of anti-cancer agents (taxol, temodal, trichostatin A) on the co-interactions of Tau with MT and actin cytoskeletons. The molecular mechanisms of Tau-MT-actin interactions will be investigated using different GBM cell models (U87 and mutant repressing Tau cells, and primary GBM cell lines GBM6 and GBM9). The methodologies of this project will involve a combination of optical instrumentation (FRET, FRAP, STORM imaging) and biological studies. Understanding the molecular mechanisms that regulate the activity of MAPs, and in particular the tau protein, in the context of tumor progression will improve fundamental knowledge about these MT regulatory proteins. From a pharmacotherapeutic point of view, the study of their role in modulating the efficacy of drugs will better predict the response to chemotherapy and possibly consider these MAPs as new targets in tumor cells. Finally, the approaches developed for this project will be decisive for the design of drugs targeting more efficiently tau and microtubules.