Debbie's Dream Foundation-AACR Career Development Award for Gastric Cancer Research
The Debbie’s Dream Foundation-AACR Career Development Award for Gastric Cancer Research represents a joint effort to encourage and support junior faculty, who will have completed their most recent medical residency or doctoral degree within the past 11 years, to conduct gastric cancer research and to establish a successful career path in this field. The research proposed for funding may be basic, translational, clinical, or epidemiological in nature and must have direct applicability and relevance to gastric cancer, specifically non-Helicobactor pylori associated gastric cancer.
Eunyoung Choi, PhD
Vanderbilt University Medical Center (VUMC)
A novel metaplastic organoid system for studying gastric carcinogenesis
Scientific Statement of Research
Gastric cancer is one of leading causes of cancer-related death worldwide. Previously, Dr. Choi has described that gastric chief cells are the origin of metaplasia and Kras activation, specifically in chief cells, can rapidly lead to metaplasia development, including intestinal metaplasia (IM) and invasive lesions. Also, inhibition of MEK, a downstream of Kras signaling, led to regression of IM and restoration of normal gastric lineages. In this study, she will investigate mechanisms of metaplasia progression to gastric adenocarcinoma using metaplastic organoids derived from active Kras-induced metaplasia, and cellular plasticity of the metaplastic organoids using a MEK inhibitor. She also plans to re-implant the metaplastic organoids to mouse stomach submucosa to determine the tumorigenic properties of metaplastic cells as a gastric cancer origin. The results from this proposed study will provide critical preclinical information to aid in designing therapeutic or preventive interventions to inhibit gastric cancer development in humans.
Dr. Choi has broad research training experiences in reproductive/embryonic biology, stem cell biology and gastric cancer biology. Since she completed graduate training in 2009 at GIST (Gwangju Institute of Science and Technology) in South Korea, Dr. Choi has worked at Vanderbilt University Medical Center, until present, and has studied a number of aspects of gastric cancer biology as a member of Epithelial Biology Center for the past four years. Currently, Dr. Choi is a research instructor at Department of Surgery and is expected to be promoted to a tenure track assistant professor in the spring of 2017.
Acknowledgement of Support
As a junior investigator, Debbie’s Dream Foundation-AACR Gastric Cancer Research Career Development Award is an important springboard for me to initiate my own research as a principal investigator and it will have a significant impact on my career. Thus, this award is critical for my successful transition to an independent investigator.
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Elise S. Demitrack,
University of Michigan
Ann Arbor, Michigan
Mechanisms of Wnt
activation in FAP gastric polyps and gastric cancer
Gastric cancer remains a critical human health problem, with a five-year survival rate less than 30 percent for patients diagnosed with this disease. Despite this poor prognosis, the mechanisms of gastric tumor initiation and disease progression from precancer to cancerous stages are poorly defined. It is currently thought that gastric stem cells that maintain adult tissue homeostasis are subject to tumor-initiating mutations, due to their rapid proliferation. Several developmental signaling pathways, such as the Wnt pathway, regulate gastric stem cell proliferation. Furthermore, it is known that patients with the Wnt-activating genetic disorder Familial Adenomatous Polyposis (FAP) develop dysplastic gastric polyps. Dr. Demitrack’s research project will focus on human gastric stem cell function in hyper-proliferative FAP gastric polyps, as well as in gastric cancer patients. Dr. Demitrack has identified the Wnt signaling pathway as necessary for proliferation of human gastric stem cells using in vitro human gastric organoid cultures. Through gene expression profiling, she has also demonstrated that Wnt pathway activity occurs in both epithelial and mesenchymal compartments of the mouse stomach, suggesting involvement of this pathway in supporting gastric stem cell homeostasis. Dr. Demitrack will use the support from the Debbie’s Dream Foundation-AACR Career Development Award to determine how the Wnt pathway regulates human gastric stem cell function in FAP gastric polyps, as well as in patients with gastric adenocarcinoma. She will use the novel 3D human gastric organoid culture system to test Wnt regulation of human gastric stem cells in organoids derived from FAP gastric polyps and gastric cancer tissues. She will perform complimentary experiments in mouse genetic models to study mechanisms of Wnt regulation of gastric stem cell proliferation. She will also use RNA sequencing technology to establish a Wnt-regulated transcriptional profile of control stomach, FAP gastric polyp and gastric cancer tissues, to identify novel gene targets that will provide insight into therapeutic targets for gastric cancer treatment. Overall, Dr. Demitrack’s research will make a significant impact into understanding how basic developmental signaling pathways, such as Wnt, lead to dysregulated stem cell proliferation and tumorigenesis in the stomach.
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