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Role of FAK in mechanotransduction

Research unit

UMR 7213 - Laboratoire de biophotonique et pharmacologie (LBP)
Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401 ILLKIRCH-GRAFFENSTADEN

Group

Name: Signalisation tumorale et cibles thérapeutiques

Group leader: DONTENWILL Monique - monique.dontenwill@unistra.fr

Group leader's phone: 03 68 95 42 67

Website: Visit website

Group organization:
- Chercheurs: 14
- ITA: 4
- Doctorants: 3
- Post-Docs: 2
- Autres: 5

Publications of the team linked to the topic (3 last years):
1) Kolli-Bouhafs K., Sick E., Noulet F., Gies J.P., De Mey J. and Rondé P.(2014) “FAK competes for Src to promote migration against invasion in melanoma cells”. Cell Death Dis. 14;5:e1379.
2) Deramaudt T.B., Dujardin D., Noulet F., Martin S., Vauchelles R., Takeda K. and Rondé P. (2014) “Altering FAK-paxillin interactions reduces adhesion, migration and invasion processes”. PLoS One 18;9(3):e92059
3) Hamadi A., Giannone G., Takeda K. and Rondé P. (2014) “Glutamate involvement in calcium -dependent migration of astrocytoma cells”. Cancer Cell Int. 19;14:42

About PhD

PhD Director: RONDE Philippe - philippe.ronde@unistra.fr

Phone: 03 68 85 41 84

Junior advisor: SICK Emilie

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Role of FAK in mechanotransduction

Project: The protein kinase FAK is an attractive therapeutic target for the treatment of many epithelial cancers since it is overexpressed in 90% of metastatic colon cancers and 80% of invasive breast cancers. In many cases, tumor invasion is associated with an increase of the rigidity of the surrounding tissues. Our project aims at identifying the potential link between tissue rigidity and tumor invasion to clarify the role of FAK in these processes.
Migration and cell invasion are determined by the formation and remodeling of specialized structures called focal adhésions and invadopodia. This dynamic process is under the control of mechano-chemical mechanisms. Indeed, the mechanical forces from the extracellular matrix cause changes in the composition of focal adhesions leading to their assembly or disassembly. Our current work focuses on the study of FAK (Focal Adhesion Kinase), a major focal adhesions kinase that plays a fundamental role in the tumorigenesis process. This project builds on our recent findings demonstrating that FAK is involved in durotaxie mechanisms, the phenomenon by which cells preferentially head to rigid substrates. We will analyze in detail mechanotransduction mechanisms and their impact on the assembly-disassembly cycle of focal adhésions and invadopodia.
First we implement force spectroscopy measurements to study intramolecular and/or intermolecular forces in play in molecules behaving as mechanosensor. To do this, we will use atomic force microscopy (AFM), a particularly suitable technique for the characterization of the conformational changes of molecules and the measurement of the forces required for these changes. This study will determine how the forces on FAK allow uncovering cryptic sites required for the transduction of a mechanical signal into a chemical signal. Secondly, to decipher the basic mechanisms of control of migration / invasion mechanisms induced by forces we develop a cellular approach using traction force microscopy (Traction Force Microscopy; TFM) to measure forces generated by cells and specialized cell structures such as focal adhesions and invadopodia. This method allows a high spatial resolution measurement of interfacial forces through the quantification and analysis of the deformation of an elastic substrate. These measures will then be coupled with measures of the dynamics of FAK and dynamics of focal adhesions to analyze the relationships between force, molecular dynamics and cell behaviour
All these data will allow us to characterize the molecular basis of mechanotransduction mechanisms and thus identify the structural units of FAK that can serve as therapeutic targets.

Wished skills: The student should be motivated by cell biology research, with basic background in molecular biology and cell biology

Expertises which will be acquired during the training: This project will allow for the acquisition of knowledge in molecular and cell biology, especially in the signalling pathways regulating cell migration and invasion.
Technical expertise will be acquired in molecular biology and biochemistry as well as advanced microscopy techniques such as 4D video-microscopy, FRET, TIRF, and FRAP imaging.