The overall aims of our studies are to increase our understanding of solid tumor metastasis by usage of the Shb-gene knockout model. These tumor processes will in particular be related to immune cell responses. The project involves both in vivo and in vitro experimentation and in an extension it is hoped that small molecular weight inhibitors of Shb function can be found that have an application in medicine.
The Shb gene in tumor biology.
Shb is an SH2-domain adapter protein operating downstream of tyrosine kinase receptors such as the VEGFR-2, FGFR-1, PDGF-receptors and the T cell receptor. The effects of Shb are pleiotropic and context dependent. We have recently generated a Shb-knockout mouse to assess the physiological relevance of Shb in vivo.
We recently made the observation that absence of Shb promotes melanoma metastasis (Zang G and all 2015) by a mechanism that involves suppression of the immune response against the tumor. We will characterize this further by performing conditional (cell-specific) Shb gene inactivation in endothelial cells, pericytes and immune cells and monitor the behavior of the tumors. This will allow us to dissect the interplay between these different cell types and thus elucidate the complex mechanisms behind promotion and suppression of tumor growth and metastasis. The analyses include flow cytometry of immune cells in the tumor, gene expression profiling and effects of different cytokines on the responses. Our working hypothesis is that endothelial cells participate in the regulation of recruitment of different classes of immune cells that may support or suppress tumor growth. The signal transduction events that regulate these responses in endothelial cells may involve FAK signaling.
Methodology: Conditional inactivation of the Shb gene, in vivo tumor growth studies, flow cytometry, cell isolation, gene expression profiling, intervention studies.