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GTPase regulated signalling pathways: role in the transition from mesenchymal to amoeboid tumor cell invasion


Malignant tumours have acquired the ability to invade surrounding tissue. One component of the invasive phenotype is increased cell motility. Two modes of tumour cell motility have been described: (i) an elongated/mesenchymal mode that requires extra-cellular proteolysis and (ii) a protease independent/amoeboid/rounded mode. Importantly, these two modes of migration are inter-convertible revealing a novel cellular and molecular adaptation pathway in the switch from a path generating to a path-finding migration mode.

The aim of this proposal is to investigate the molecular mechanisms underlying this switching process. Several different conditions will lead to switching. Tumour cells that migrate in a 3D matrix with an elongated phenotype switch to rounded/amoe boid mode in the presence of protease inhibitors. Conversely, it has been demonstrated that cells, which move in the rounded/amoeboid fashion will convert to elongated movement in the presence of myofibroblasts. Furthermore, cells can be made to switch between rounded and elongated morphology by plating matrices of different rigidity. Rigid non-deformable matrices favour the elongated morphology while deformable matrices favour a rounded morphology.

The aim of this project is to identify (i)changes in gene expression leading to changes in cell morphology and mode of cell movement and to identify (ii)signalling pathways driving the changed morphology. These are important questions since the ability to switch modes of movement has important implications for the rapies to stop tumour cell invasion and thus metastasis.

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