SIGNALING IN INTESTINAL CANCER

Project: Research project

Project Details

Description

Altered Notch signaling is fundamental in development of colon cancer and colon tumor phenotype, and is an important target for prevention and therapy. These roles stem from two important functions of Notch signaling in the intestine: first, its cooperation with Wnt signaling in maintaining a proliferating- progenitor cell phenotype of intestinal crypt cells, and second, again in cooperation with Wnt, in allocating cells to specific lineages as they exit the proliferative compartment during their maturation along the crypt-luminal axis. In Aim 1, we will determine how Notch signaling, and its coordination with Wnt signaling, is regulated along the crypt-luminal axis in the normal mouse large and small intestine, and perturbations that arise along this axis in the Apc1638+/- genetically initiated mouse model of intestinal cancer, and in the first nutritional mouse model of sporadic colon cancer (Yang et al, Cancer Res, 2008). This will utilize novel techniques that will also determine how genetic inactivation of Notch or Wnt signaling alters the complementary pathway and cell maturation and homeostasis along the crypt-lumen axis, and how this progresses spatially and temporally following gene inactivation. Gene inactivation specifically in the intestine will be done in 2 models: a) conditional deletion of Pofut1flox/flox, the fucosyltransferase necessary for efficient signaling through all Notch receptors, that we have recently shown inhibits intestinal Notch signaling, causing secretory cell metaplasia, inflammation and dysplasia (Guilmeau et al, Gastroenterology, 2008);b) conditional intestinal deletion of Apcflox/flox . Finally, we will extend these aims to specifically focus on expression of Jagged1, a specific ligand for Notch receptors whose expression is driven by Wnt signaling in tumors and that we have found aberrantly expressed in mouse and human intestinal tumors. Aim 2 is based on preliminary data that expression of Notch signaling components and effectors is heterogeneous in mouse intestinal tumors, and that Jagged1 is aberrantly overexpressed more frequently in tumors of Apc1638 mice compared to tumors of ApcMin mice. To pursue this, we will utilize tissue from patients in large, well-defined human pedigrees of the Univ. of Utah Familial Colon Cancer Registry. These pedigrees encompass both classical familial polyposis and attenuated familial polyposis. In each pedigree, the nature of the APC mutation is either already known or can be readily ascertained, and there is continuous clinical follow-up. We will use both archived tissue to assess the extent of inter- and intra-tumor heterogeneity of Notch signaling and expression of underlying components of the pathway, especially Jagged1, and determine if this is a function of the nature of the Apc mutation.
StatusFinished
Effective start/end date7/17/096/30/10

Funding

  • National Cancer Institute: $331,094.00

ASJC

  • Gastroenterology
  • Molecular Medicine
  • Cancer Research
  • Developmental Biology
  • Immunology

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