Several recent conceptual advances in cancer biology, such as the concept of tumor stem cells, or the recognition that developmental signaling pathways can be oncogenic when misregulated, have arisen from the convergence of the fields of cancer and developmental biology. The highly conserved Wnt/beta-catenin signaling pathway is particularly exemplary as it is a crucial pathway for embryogenesis, and causes cancer when ectopically activated in the adult. Mutations in oncogenes or tumor suppressors identified in this pathway lead to its constitutive activation. Alternative Wnt signaling pathways, stimulated by Wnt5a, have been shown to antagonize Wnt/beta-catenin signaling suggesting that these pathways could function to suppress tumorigenesis.As described in our other project analysing the Wnt3a/bcatenin pathway during embryogenesis, we have identified a large number of target genes of this pathway that function in the embryo. Some of these genes, such as c-myc and Lef1, are known to regulate oncogenic transformation and to be highly expressed in colorectal tumors. We propose that our screen for new developmental Wnt/beta-catenin target genes has enriched for potential oncogenes. We are currently assessing the expression of these Wnt target genes in colorectal cancers caused by an activated Wnt/?catenin pathway, as well as performing several functional assays in vitro. We expect to identify several new Wnt-regulated oncogenes and tumor suppressors, and gain a better understanding of how aberrant Wnt signaling promotes cancer. We have also discovered that mutations that affect alternative Wnt signaling pathways can enhance cancers of the immune system. Our data indicates that Wnt5a functions as a haploinsufficient tumor suppressor, suppressing T cell lymphoblastic leukemia by repressing Runx1. These genetic interaction studies have led to the development of a mouse model of T-cell lymphoma. This work has been written up and is about to be submitted.
| Tsukiyama, Tadasuke; Yamaguchi, Terry P (2012) Mice lacking Wnt2b are viable and display a postnatal olfactory bulb phenotype. Neurosci Lett 512:48-52 |
| Joesting, Margaret S; Cheever, Thomas R; Volzing, Katherine G et al. (2008) Secreted frizzled related protein 1 is a paracrine modulator of epithelial branching morphogenesis, proliferation, and secretory gene expression in the prostate. Dev Biol 317:161-73 |
| Warming, Soren; Suzuki, Takeshi; Yamaguchi, Terry P et al. (2004) Early B-cell factor-associated zinc-finger gene is a frequent target of retroviral integration in murine B-cell lymphomas. Oncogene 23:2727-31 |
