PPM1D: The new marker for intestinal stem cells and its role in tumorigenesis.

C5 Colorectal cancer is one of the major causes of cancer-related deaths. To gain further insights into the mechanisms underlying its development, we investigated the role of Wip1 (PPM1D) oncogene using a genetically defined mouse model of APCMin-driven polyposis. We found that the removal of Wip1 phosphatase increased the life-span of APC(Min) mice through a drastic suppression of polyp formation. This protection was dependent on the p53 tumor suppressor, while WNT-beta-catenin pathway, the major driving force in APC(Min) tumorigenesis, was not affected by Wip1 removal. We observed that Wip1 phosphatase was highly expressed in intestinal stem cells (ISC). The long life and rapid rate of cell division make ISC primary candidates for conversion into cancer stem cells through the accumulation of genetic defects associated with cancer induction In Wip1 deficient, but not wild-type, APC(Min) mice ISC undergo p53-dependent apoptosis that significantly increased when the Wnt pathway was constitutively activated, thus eliminating cells with higher oncogenic potential. We propose that Wip1 modulates APC(Min) -driven polyposis by setting a threshold for p53-dependent apoptosis of stem cells, thus preventing their conversion into cancer stem cells.