The Drosophila Hippo pathway regulates organ size through regulation of the transcriptional activator Yorkie. Interestingly, expression of the mammalian ortholog of Yorkie, YAP1, is enriched in stem cells and amplified in cancer. Our long-term goal in this project is to gain insight into the role of the Hippo signaling pathway in mammalian organ size control, stem cells and cancer. The specific hypothesis is that the Hippo pathway acts on stem cell compartments and expands undifferentiated progenitor cells when needed during tissue growth, and during tumorigenesis.
The specific aims are: 1. Effect of Hippo pathway on stem cells. We will analyze effects of YAP1 on intestinal stem cells in vitro and in vivo. 2. Role of YAP1 on tumorigenesis. YAP1 activation leads to uncontrolled expansion of progenitor cells. We will analyze how YAP1 activation impacts on tumorigenesis and the requirement for YAP1 to maintain a cancerous state. 3. Identify downstream effectors of YAP1. YAP1 acts as a transcriptional coactivator. Preliminary data suggests that this may involve the Notch signaling pathway. We will analyze which transcription factor and transcriptional targets it activates.
The barrier that normal tissues encounter when they have reached the correct size is likely to impact on the very early stages of tumorigenesis. Here we propose to elucidate how a pathway that regulates organ size in mammals controls stem cells, which are thought to be key players in tumorigenesis, and is deregulated in cancer. A more complete understanding of how activity of this pathway is controlled during development and deregulated during tumorigenesis may highlight suitable targets for future cancer therapeutics.
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