Our team is interested in the molecular mechanisms underlying the appearance, survival and proliferation of cancer cells, and their dissemination. More specifically, by studying signalling networks, we aim to identify novel cellular targets with the therapeutic potential of differentiating between normal and cancer cells.
One of the most frequently mutated gene products in human cancers is the Ras protein. Its constitutive activation causes a cascade of intracellular signals whose components required for cancerous transformation has long been debated. The less studied among these cascades are the so-named “Ral driven signalling networks”, mobilized downstream of Ras by another GTPase, Ral, as shown both in experimental oncology and in human cancers. The activity of our team is organized around the question of the role of the Ral GTPase in oncogenic transformation and in physiological homeostasis.
The Ral GTPases have progressed from a status of molecular curiosity, appearing in evolution with metazoans and subsequently conserved in Homo sapiens, to the status of key player in oncogenesis. Ral exists neither in plants, nor in single-cell organisms. It is an essential link for the hyper signalling driven by oncogenic deregulated receptors or Ras mutants. Even better: cancer cells appear to be extremely susceptible to a drop in Ral activity, as this leads to their death.
We followed two parallel approaches relying on the known functional and physical conservation of the Ral signalling pathways between flies and mammals. We used Drosophila as a model organism for our genetic approach. We use biochemistry and cell biology techniques on vertebrate cells harbouring defined properties of “normal” or transformed cells for our cellular approach. Presently our efforts are exerted along two lines: the stamp collector approach and the hypothesis driven approach.
We were able to identify proteins organized in networks (figure 1) and involved in oncogenic Ras transduction routes. We have achieved this by a molecular approach via the Drosoman screening project aimed at defining the protein-protein interaction map of more than 150 proteins of critical importance to oncogenesis or to cell life. A genetic screen in Drosophila has completed this data set: starting from cell death caused by a Ral mutation, we have identified a number of genes that either exacerbate the death rate, or conversely prevent death. Our aim is now to define the properties of these gene/protein partnerships. To do so, we are using a combination of cell biology, molecular biology, biochemistry and fly genetics methods together with High Content Screening approaches by automated cell imaging (The Biophenics platform).
After spending some time in deciphering Ral contribution to cytokinesis (figure 2) two main biological functions are phagocyting our efforts: 1) autophagy, where Ral GTP ases appear to be required and instructive, and the relationship of which to oncogenesis remains to be clarified both for at basic understanding and for pharmacological purposes, 2) anoikis : a remarkable and specific capacity of cancer cells to dodge death upon extra-cellular matrix detachment (notice that the corresponding in vitro assay -colony growth in soft agar- is a not so bad surrogate assay for tumorigenesis).