Beta-catenin as a regulator of cancer cell survival

The cells lining many human organs (epithelial cells) form a single layer. Cells that detach from this layer die. Cancer cells are often derived from epithelial cells. To be able to form three-dimensional tumors and spread throughout the body cancer cells have to be able to survive outside of the epithelial layer. Understanding the mechanisms that control their survival is necessary for designing cancer treatment based on killing tumor cells outside of their original location. Many proteins that drive cancer progression trigger not only survival but also death signals in tumor cells. The survival signals prevail in these cells. It is now thought that treatments blocking the survival signals but preserving the death signals can be particularly effective in killing tumor cells. Whether or not tumor cells that are detached from the original epithelial layer carry any death signals that can be used for enhancing the efficiency of approaches aimed at killing them has never been explored. To this end, we are studying a protein called beta-catenin, which contributes to the progression of many cancers. Genetic alterations in tumor cells activate beta-catenin and allow it to trigger signals that rescue detached cells from dying. A protein called Tumor Necrosis Factor Receptor 1 (TNFR1) is known to block cell death. We have found recently that in addition to survival signals, beta-catenin induces a death signal in tumor cells. This signal is mediated by beta-catenin-dependent loss of TNFR1. We will test in the proposed study whether colon cancer cells are killed outside of their original location if beta-catenin is removed from these cells and whether they are killed even more efficiently if beta-catenin-induced death signal mediated by TNFR1 loss is preserved in these cells after beta-catenin is removed. If successful, our work could provide mechanistic basis for the design of novel therapies aimed at blocking the survival of cancer cells outside of their original location.