Secreted Hedgehog (Hh) ligands play important roles in growth and patterning of various tissues during development, and recent studies have uncovered transient reactivation of Hh signaling during injury and repair of several adult tissues. There is compelling evidence that sustained Hh signaling, which may be initiated during an aberrant response to injury, is associated with a wide variety of human malignancies. Moreover, uncontrolled Hh pathway activity may be required for tumor maintenance, since blockade of Hh signaling inhibits the growth of several types of 'Hh-activated'tumor cells. It has been proposed that only those cell types which utilize the Hh pathway during embryogenesis or repair are prone to Hh pathway-associated tumorigenesis, but this concept has not been rigorously tested. Gastric cancer is the 2nd most common cause of cancer mortality worldwide, and the great majority of gastric tumors are associated with elevated Hh signaling activity, attributed to abnormally high expression of the Hh ligands Sonic hedgehog (Shh) and/or Indian hedgehog (Ihh). We have generated a robust model of gastric adenocarcinoma by constitutively activating Hh signaling in mouse stomach, pointing to a causal role for deregulated Hh signaling in the pathogenesis of these aggressive tumors in humans. However, there is presently little insight into how aberrations in Hh signaling contribute to gastric tumorigenesis, which progenitor cells give rise to 'Hh-activated'gastric cancers, and whether Hh signaling is required for maintenance of established tumors. Moreover, the precise functions of Hh signaling in normal stomach have not yet been established, and there is a little information regarding changes in Hh signaling activity during gastric injury and repair, which can predispose to cancer development.
In Aim 1, we propose to identify the cell types expressing Hh pathway components, and determine the function of Hh signaling, in normal and pathologically altered stomach.
In Aim 2, we will explore the function of Hh signaling in gastric tumor biology and maintenance. The proposed studies will provide new insights into the functions of Hh signaling in normal and injured stomach, and the role of deregulated Hh signaling in the pathogenesis of gastric cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118875-05
Application #
8080875
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Mietz, Judy
Project Start
2007-07-13
Project End
2012-11-30
Budget Start
2011-06-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$264,802
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dermatology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
Liu, Hong Xiang; Ermilov, Alexandre; Grachtchouk, Marina et al. (2013) Multiple Shh signaling centers participate in fungiform papilla and taste bud formation and maintenance. Dev Biol 382:82-97
Syu, Li-Jyun; El-Zaatari, Mohamad; Eaton, Kathryn A et al. (2012) Transgenic expression of interferon-? in mouse stomach leads to inflammation, metaplasia, and dysplasia. Am J Pathol 181:2114-25
Saqui-Salces, Milena; Cov├ęs-Datson, Evelyn; Veniaminova, Natalia A et al. (2012) Inflammation and Gli2 suppress gastrin gene expression in a murine model of antral hyperplasia. PLoS One 7:e48039
Eberl, Markus; Klingler, Stefan; Mangelberger, Doris et al. (2012) Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells. EMBO Mol Med 4:218-33