The neoplastic Tumor Suppressor Genes (nTSGs) are a group of genes initially identified with genetic screenings in Drosophila (fruit fly). Mutations of nTSGs lead to loss of epithelial polarity and transform the mutant cells into highly proliferative and invasive tissue. Importantly, the mammalian homologs of Drosophila nTSGs show highly conserved functions in epithelial organization and proliferation control. In a genetic mosaic experiment, we noticed that nTSG mutant cells underwent over proliferation in folded epithelial regions while they were eliminated through cell competition in a flat epithelial sheet. The epithelial architecture-dependent variation of tumor development has also been reported in human carcinoma cases. These evidence points to our hypothesis that epitheli...[ Read more ]

The neoplastic Tumor Suppressor Genes (nTSGs) are a group of genes initially identified with genetic screenings in Drosophila (fruit fly). Mutations of nTSGs lead to loss of epithelial polarity and transform the mutant cells into highly proliferative and invasive tissue. Importantly, the mammalian homologs of Drosophila nTSGs show highly conserved functions in epithelial organization and proliferation control. In a genetic mosaic experiment, we noticed that nTSG mutant cells underwent over proliferation in folded epithelial regions while they were eliminated through cell competition in a flat epithelial sheet. The epithelial architecture-dependent variation of tumor development has also been reported in human carcinoma cases. These evidence points to our hypothesis that epithelial curvature is an important factor determining the phenotypic outcomes of nTSG mutations.

To test this hypothesis, we developed methods to manipulate the mechanical properties of epithelial cells and observed that increase of cellular tension led to ectopic fold formation and promoted nTSG mutant cell growth in the flat epithelium. We also show the activation of JAK/STAT pathway is necessary for the survival and growth of the mutant cells. In addition, we show that diverse curvature of epithelial cell sheets leads to different actomyosin activity and Yki activity, indicating that epithelial curvature may influence nTSG mutant cell growth outcomes through modulating Yki activity. Our study provides a new insight into the carcinogenesis where biomechanical signals can play a significant role.

Keywords: nTSGs Fly tumor Curvature JAK/STAT pathway Yki