Most cancers originate from epithelial cells that have pronounced apico-basal polarity. Loss of cell polarity in these cells triggers abnormal proliferation that can lead to cancer development. Interestingly, recent studies have revealed that normal epithelial tissues have an intrinsic tumor suppression mechanism that eliminates oncogenic polarity-deficient cells from the tissue. We have previously found that clones of cells mutant for evolutionarily conserved apico-basal polarity genes, such as scribble or discs large, are eliminated from Drosophila epithelial tubular tissue though cell-cell communication. However, molecular mechanism of such intrinsic tumor suppression is poorly understood. In this project, by using Drosophila genetics, we will challenge to understand the mechanism of how normal cells recognize and eliminate oncogenic neighbors.

We have established the non-cell autonomous genetic screen system for identifying factors that causes elimination of oncogenic polarity-deficient cells from the tissue. Using this novel non-cell autonomous genetic screen system, we will screen mutations that fail to eliminate polarity-deficient cells, as well as mutations that enhance the elimination of polarity-deficient cells. Once several mutations are recovered, we will start to identify responsible genes of each mutant and address the role of these genes in cell elimination.

There are growing evidence suggesting that cell-cell communication has important roles in tumor suppression mechanism that eliminate a newly emerged oncogenic cells from epithelial tubular tissues. However, molecular basis of how tumor suppression mechanism through cell-cell communication works in whole animal is still unclear. Our analyses using powerful Drosophila genetics will dissect the mechanism of cell-cell communication between normal cells and polarity-deficient oncogenic cells in epithelial population, which will contribute to understand the basis of epithelial intrinsic tumor suppression. Furthermore, our study could contribute to development for new therapeutic approaches against cancers.