- Email Address
- [email protected]
- Research Description
Cells communicate with each other through signaling pathways, many of which are involved in processes such as development and the onset and progression of disease. In my lab, we focus on the Wnt signaling pathway, since over 90% of colorectal cancers are caused by mutations in this pathway. I am curious to know how this pathway can turn itself on and off so many times during development and why it fails to turn off in disease.
- Research Summary
Many of the signaling pathways that are involved in development are also involved in the onset and progression of disease. As an example, the Wnt signaling pathway is required during many stages of development and in the homeostasis of stem cells in the adult. Perturbation of this pathway in stem cells in the adult often leads to cancer. It is now known that greater than 90% of colorectal cancers are caused by mutations in the Wnt signaling pathway. As this pathway is important for both proper development and disease, I am curious to know how this pathway can turn it self on and off so many times during development and why it fails to turn off in disease.
The lab focuses on two negative feedback regulators of Wnt signaling: Nkd1 and Axin2. Both of these are induced by Wnt signaling and so far appear to be obligate and universal targets of Wnt signaling within vertebrates. Using zebrafish as as in vivo cell models, we are testing the hypothesis that Nkd1 is somehow activated on the plasma membrane by a Wnt ligand. Upon activation, Nkd1 moves from the membrane into the cytoplasm to inhibit the nuclear accumulation of ?-catenin, which is the central signaling molecule of the Wnt pathway. Due to the nuances of cell culture we cannot observe this phenomenon in vitro, but have found that Nkd1 can be artificially activated in cancer cells, potentially inhibiting their growth. Currently, we are trying to determine how Nkd1 is activated and what affect this has on the cancer cells. We are also studying Axin2, which is expressed at the same time and in the same place as Nkd1. We have evidence that Nkd1 and Axin2 cooperate, but by itself Axin2 is a very potent inhibitor of Wnt signaling that doesnt need activation.
- Techniques Used
Cancer cells for in vitro analysis; zebrafish embryos for in vivo analysis; CRISPR technology.