December 6, 2017

Drivers of Intestinal Tumorigenesis

​A hallmark of all epithelia is the presence of adherens junctions that connect adjacent cells to each other. The junctions are formed through the interaction of the extracellular domains of E-cadherin on the neighboring cells. In turn, the intracellular domain of E-cadherin forms a complex with other proteins, including p120-catenin (p120), α-catenin, and β-catenin, that provides a link to actin filaments in the underlying cytoskeleton. Considerable evidence supports a role for E-cadherin and other adherens junction proteins as tumor suppressors.  Now, work from Basic Sciences investigator Albert Reynolds, along with his collaborators, Robert Coffey (Department of Medicine), Nancy Jenkins and Neal Copeland (Methodist Hospital Research Institute, Houston, TX), and Michael Payne (Chulalongkorn University, Bangkok), provides important new insight in the role of p120 in tumor suppression. Their work focused on mouse models of intestinal tumorigenesis driven by mutations in the gene encoding the adenomatous polyposis coli (APC) protein. The investigators created a new model in these mice in which the gene for p120 could be selectively knocked out in the intestine to varying degrees. They discovered that knockout of p120 led to a substantial increase in tumors in the mice. However, the tumors that were generated consistently contained one wild-type and one knocked out p120 gene; there were no tumors in which p120 expression was totally ablated. Further work showed some regions in the intestines that exhibited a total loss of p120, but all of these were normal epithelium. Time course studies revealed the presence of regions of total p120 loss in early tumor formation, but these were lost over a period of several weeks. When the researchers established APC-driven tumor organoids in culture, they discovered that total knockout of p120 led to a marked increase in proliferation and a change to a branched morphology, but the organoids exhibited rapid death by apoptosis unless an inhibitor of Rho kinase was also present in the culture medium. The results indicate that reduction of p120 levels due to loss of one gene for the protein promotes APC-driven tumorigenesis, but complete loss is fatal to tumor cells. Further work using the Sleeping Beauty transposon to detect gene derangements that drive intestinal tumorigenesis indicated that deficiencies of p120, E-cadherin, and α-catenin are all very strong tumor drivers. The findings provide important new information for the design of therapies directed towards mechanisms that specifically lead to cancer in the intestinal tract. The work is published in the Journal of Clinical Investigation (S. P. Short et al. J. Clin. Invest., 2017, doi:10.1172/JCI77217).