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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA131426-06
Application #
8403498
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
6
Fiscal Year
2013
Total Cost
$204,335
Indirect Cost
$15,136
Name
Netherlands Cancer Institute
Department
Type
DUNS #
419693502
City
Amsterdam
State
Country
Netherlands
Zip Code
1066 -CX
Mohseni, Morvarid; Sun, Jianlong; Lau, Allison et al. (2014) A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol 16:108-17
Mori, Masaki; Triboulet, Robinson; Mohseni, Morvarid et al. (2014) Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell 156:893-906
Halder, Georg; Camargo, Fernando D (2013) The hippo tumor suppressor network: from organ size control to stem cells and cancer. Cancer Res 73:6389-92
Barry, Evan R; Morikawa, Teppei; Butler, Brian L et al. (2013) Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493:106-10
Schlegelmilch, Karin; Mohseni, Morvarid; Kirak, Oktay et al. (2011) Yap1 acts downstream of ?-catenin to control epidermal proliferation. Cell 144:782-95