Barrett?s esophagus (BE) is the only known pre-cancer lesion of esophageal adenocarcinoma (EAC) which has seen a 600% increase in incidence. However, the cellular and molecular mechanism driving BE initiation and progression remains undetermined, and the knowledge gap prevents us from identifying meaningful therapeutic targets for the treatment of the pathological entity. This application will build on our recent findings that the novel transitional basal stem cells contribute to Barrett?s metaplasia in both mouse genetics and human organoid models. We will study the molecular mechanism promoting the intestinal differentiation of the unique stem cell population. Our preliminary data suggest that Wnt signaling and its downstream target SOX4 play critical roles in the pathogenesis of BE. Therefore we will test the hypothesis that the Wnt/SOX4 axis promotes Barrett?s metaplasia and that pharmacological inhibition of the axis blocks BE progression. We have designed three aims to test this hypothesis: (1) To test the hypothesis that increased Wnt signaling upon chronic inflammation promotes Barrett?s metaplasia of transitional basal stem cells. (2) To test the hypothesis that SOX4 mediates Wnt signaling to promote Barrett?s metaplasia, and (3) To intervene in the Wnt/SOX4 axis for therapeutic gain against BE and EAC. We will use multiple mouse models (e.g. Wnt and SOX4 gain- and loss-of-function) combined with organoid and in vitro assays to address these aims and test candidate drugs identified through an unbiased screen. This work will provide novel insights into the cellular and molecular mechanisms underlying the initiation and progression of BE, and the signaling program we identified will enable discovery of new therapeutic targets.

Public Health Relevance

Barrett?s esophagus is a strong risk factor for esophageal adenocarcinoma which has become the most rapidly increasing cancer in the United States. The mechanism promoting Barrett?s metaplasia, however, remains unknown. This proposal will determine how the Wnt/SOX4 axis drives Barrett?s pathogenesis, meanwhile testing drugs that block the axis for potential therapeutic gains against the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK120650-03
Application #
10129373
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hamilton, Frank A
Project Start
2019-05-20
Project End
2023-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032