Autophagy mediator Beclin 1 as a suppressor of three-dimensional growth of ras oncogene-driven tumors

The cells lining many human organs (epithelial cells) form a single layer. Cells that detach from this layer die. Most tumors are composed of epithelial cells that became cancerous. These cells now have to survive outside of the epithelial layer in order to be able to form a three-dimensional tumor mass and spread throughout the body. We are investigating the mechanisms allowing detached cancer cells to survive. Cellular protein called Ras is normally activated by signals coming from outside of the cell. Ras can, in turn, trigger events that change cellular levels of many proteins. Genetic alterations in cancer cells can make Ras active at all times and this contributes to the progression of many cancers. One of the properties of Ras that is thought to make it a major factor in cancer is its ability to block death of tumor cells growing outside of the epithelial layer. We have begun to identify the mechanisms of this effect of Ras but our knowledge about these mechanisms is far from complete. We found recently that Ras triggers the reduction in the levels of a cell death-inducing protein called Beclin 1 in cancer cells. The role of Beclin 1 in the Ras-driven survival of cancer cells growing outside of their original location has never been explored. We will examine this role in the present study. We expect that re-introduction of Beclin 1 into cancer cells will block Ras-dependent survival and growth of these cells outside of the epithelial layer and prevent growth of Ras-driven tumors in mice (which are often used as models for studying tumor growth). We expect that our studies will reveal the mechanisms allowing tumors to grow outside of the epithelial layer. Suppression of these mechanisms can be anticipated to stop or slow down tumor progression. If successful, our work could give rise to a new type of cancer therapy based on blocking the formation of the three-dimensional tumor mass and the spread of cancer cells throughout the body.