This application requests funds to support the postdoctoral training of Dr. Elise Demitrack in the field of gastric stem cells, epithelial cell homeostasis and gastric cancer biology. Cancer cell proliferation and tumor progression are affected by fundamental signaling pathways that regulate both normal tissue homeostasis and tumor growth. This proposal focuses on the Notch signaling pathway, which is known to regulate cellular processes such as stem/progenitor cell proliferation, cell survival/apoptosis and cell differentiation in several tissues, yet has not been described for the stomach. My preliminary studies in mouse models and cultured human gastric cancer cell lines demonstrate that Notch regulates gastric epithelial cell proliferation and differentiation. Moreover, analysis of the recently characterized gastric antral stem cell marker Lgr5 showed a marked decrease in expression in mice with Notch signaling inhibited, suggesting that Notch is critical for maintenance of stem cells in the stomach antrum. This proposal will test the following hypothesis: Notch signaling supports the proliferation and survival of gastric stem cells as well as proliferation of gastric cancer cells. To address this hypothesis, pharmacologic and genetic tools will be used to manipulate Notch pathway components in antral epithelial cells. Mouse strains expressing Cre recombinase driven by lineage specific gastric promoters will be crossed with genetic models of Notch activation or Notch disruption to study how Notch signaling regulates gastric epithelial stem cell survival, proliferation and lineage commitment. Analysis of Notch in gastric tumors will take advantage of established human gastric cancer cell lines, as well as the gastrin- deficient mouse model previously generated by the Samuelson laboratory, which spontaneously develops antral adenocarcinomas.
Two specific aims are proposed: (1) Test the hypothesis that gastric antral stem cells are regulated by Notch signaling to maintain tissue homeostasis, through (1A) direct targeting of the Lgr5-positive antral stem cell and/or (1B) through regulation of antral epithelial cell fate;(2) Test the hypothesis that antral tumors are sustained through Notch-regulated proliferation of Lgr5-expressing stem cells, by (2A) performing lineage tracing of antral tumors in gastrin-deficient mice and (2B) determining the role of Notch for tumor growth in mouse models and human gastric cancer cells. Together, these studies will provide an excellent training experience in basic signaling pathways regulating gastric cancer to position the applicant for a career in gastric cancer biology.
Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related mortality worldwide. Because the Notch signaling pathway has been shown to play a role in solid tumor development in breast and colon cancers, we postulate that Notch activity may also regulate gastric cancer cell proliferation. This project will determine how Notch activity regulates the gastric antral stem cell, as well as gastric cancer stem cells in the gastrin-deficient mouse model, which develops spontaneous antral tumors.
|Syu, Li-Jyun; Zhao, Xinyi; Zhang, Yaqing et al. (2016) Invasive mouse gastric adenocarcinomas arising from Lgr5+ stem cells are dependent on crosstalk between the Hedgehog/GLI2 and mTOR pathways. Oncotarget 7:10255-70|
|Gifford, Gail B; Demitrack, Elise S; Keeley, Theresa M et al. (2016) Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut :|
|Demitrack, Elise S; Gifford, Gail B; Keeley, Theresa M et al. (2015) Notch signaling regulates gastric antral LGR5 stem cell function. EMBO J 34:2522-36|