RESEARCH SUMMARY

The Ras GTPase is mutated in approximately 15% of human tumours, and these mutations are especially frequent in lung, colon and pancreatic carcinomas. In normal cells, Ras participates in several biological responses, regulating cell cycle progression, migration, differentiation and cell survival as well as immune system development and function. Ras mediates these functions through the activation of three effector pathways, Raf/MAPK, PI3K and the Ral GTPases. The focus of our research is to analyse the contribution of these Ras effectors to several aspects of inflammation and tumour development.

We analyse the role of Ral GTPases in the immune system using genetically modified mice and biochemical tools to knock down the expression of these GTPases. In cytotoxic cells, both Ral isoforms, RalA and RalB, are activated rapidly after target cell recognition, and translocate to the cell-cell contact zone. A critical step in cell-mediated cytotoxicity is the directed secretion of lytic granules at the immunological synapse, by which lytic molecules are delivered specifically to the target cell, and neighbouring cells are protected from damage. Ral GTPases have been shown to participate in polarized secretion in different cell types; we therefore study Ral function in the regulation of cell-mediated cytotoxicity.

A large body of evidence now supports a correlation between inflammation and cancer, although the molecular mechanisms that govern this process are poorly understood. This correlation is particularly clear in patients with inflammatory bowel disease, who have an increased risk of developing colorectal cancer. We use a murine model of inflammatory bowel disease to dissect the contribution of a PI3K isoform, PI3Kγ, to inflammation-associated colorectal cancer. We found that PI3Kγ-deficient mice had lower incidence and multiplicity of tumours than control mice. PI3Kγ^-/- animals also showed a reduction in colon inflammation levels, with defective activation and infiltration of myeloid cells and, in consequence, defective recruitment of T cells to the colon. These data suggest that PI3Kγ ameliorates inflammation-associated cancer by modulating the immune response.

By understanding the molecular mechanisms that regulate different steps during tumour formation, we can contribute to finding potential targets for the development of new cancer treatment therapies.