It has been revealed that when transformed cells are produced in an epithelial tubular tissue, they can be eliminated from the epithelial monolayer by "cell competition" between transformed cells and surrounding normal cells. However it remains unclear whether cell competition also occurs in our mammalian body. Therefore we established a novel mouse model and revealed that cell competition-mediated elimination of transformed cells actually happened in vivo. In this research project, we challenge to clarify the role of cell competition in not only the maintenance of epithelial tubular structures but also carcinogenesis by utilizing this novel mouse model.

It is widely accepted that cancers arise through the sequential accumulation of mutations that activated oncogenes or disrupt tumor suppressor genes. This implies that cell competition as an anti-oncogenesis machinery should be dysfunctioned as multi-step carcinogenesis progresses. Thus, we investigate how cell competition is affected in the common colon cancer model which is associated with the sequential genetic mutations (APC→K-ras→p53). To address this issue, we establish a novel cell competition mouse model to see the fate of APC/K-ras double mutated cells surrounded by APC-mutated cells by crossing the mice in which KrasV12-transformed cells can be induced by Tamoxifen injection in the colonic epithelia in a mosaic manner with APC^min mice. We will evaluate the behavior of K-rasV12/p53 double mutated cell as well.

It had been largely unknown whether cell competition really contributes to the clearance of transformed cells in vivo since the appropriate mouse model had not been established. Since we have recently established the cell competition mouse model, we are able to address whether cell competition is truly involved in the maintenance of tubular structural homeostasis and tumorigenesis. In this project, we approach this issue by elucidating the role of cell competition in multi-sequential carcinogenesis. The outcome of this research would contribute to the understanding why the specific order of genetic mutations is required for tumorigenesis, which has been one of biggest questions in cancer biology. It can be also applied to study the very initial molecular events in carcinogenesis. By further developing this new research field, we would create a novel type of cancer treatment.