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GRANTEE: GLORIA SU, PHD
Institution: Columbia University
Research Project: Notch Decoy Signaling in Pancreatic Cancer Stem Cells
Award: 2010 Pancreatic Cancer Action Network – AACR Innovative Grant
Award Period: July 1, 2010 – June 30, 2012
Amount: $200,000
Click here to download Dr. Su’s 2010 Grant Snapshot (pdf)
Institution: Columbia University
Research Project: Activin Signaling in the Development of Pancreatic Cancer Precursor Lesions
Award: 2007 Pancreatic Cancer Action Network Pilot Grant
Award Period: July 1, 2007 – June 30, 2008
Amount: $60,000
Click here to download Dr. Su’s 2007 Grant Snapshot (pdf)
Biographical Highlights
After receiving her PhD in Immunology from University of Chicago, Dr. Su relocated to Johns Hopkins University where she first completed a postdoctoral fellowship in Cancer Genetics/Pancreatic Cancer. She then became an Instructor in the Department of Pathology and, in 2001, was promoted to Assistant Professor. In 2003, she joined Columbia University College of Physicians and Surgeons as an Assistant Professor in the Departments of Otolaryngology/Head & Neck Surgery, and Pathology. Her research interests include genetic profiling and mouse modeling for pancreatic cancer. Dr. Su is a two-time recipient of a Pancreatic Cancer Action Network Grant. In 2007, she received a Pilot Grant for her research titled Activin Signaling in the Development of Pancreatic Cancer Precursor Lesions. Dr. Su serves on the editorial board of the International Journal of Gastrointestinal Cancer and has served as a grant reviewer for the National Institutes of Health, Department of Defense – Congressionally Directed Medical Research Programs, Italian Ministry of Health, and Cancer Council NSW Australia.
2010 Project Overview
Notch is a protein known to play a vital role in the development of numerous tissues, including pancreatic, and then is turned off in adult tissues. However, pancreatic cancer cells aberrantly reactivate Notch signaling, leading to cell differentiation and proliferation. Notch comprises a family of four receptors, and numerous proteins that bind to and activate those receptors. The focus of Dr. Su’s study is to evaluate a novel method of blocking Notch.
Initial studies will involve deleting the Notch gene itself from both the tumor and surrounding cells in a mouse model of pancreatic cancer, and determining if this protein’s presence is necessary for tumor development and maintenance. Then, Dr. Su and colleagues will explore whether a Notch “decoy” can exclusively impede the Notch signaling pathway. This decoy physically prevents Notch receptors from binding to their activating proteins, representing a novel strategy, as opposed to previously described inhibitors that less specifically block an entire family of similarly signaling molecules. Dr. Su’s experimental approach provides promising therapeutic potential by obstructing an important signaling pathway in pancreatic cancer.
2007 Project Description
Previous research has shown that the activin signaling pathway is important for human pancreatic tumorigenesis, although it has not been studied in vivo (i.e., using whole organisms). Genetic engineered mice have been effective tools for cancer modeling and cell pathway studies. In the funded project, genetic engineered mice are used to study the activin signaling pathway and its role in pancreatic cancer. Preliminary data show that the inactivation of the activin pathway in combination with the activation of Kras can lead to the development of mucinous cystic lesions in the pancreases of the mice. Plans are to use the mice to examine tumorigenesis from non-invasive mucinous cystic precursor lesions to invasive cancer in human pancreases. The results are expected to further our understanding of the three common precursor lesions: PanIN (pancreatic intraepithelial neoplasias), IPMN (intraductal papillary mucinous neoplasms), and MCN (mucinous cystic neoplasm), at the onset of pancreatic tumorigenesis.
Results/Outcomes
Following are key results of the study: (a) the mouse model used in the study simulated human IPMN; (b) IPMN-like lesions in the mice were found to be able to progress to invasive cancer and metastasis; (c) the time line and survival curve that correlate with disease progression in the model were determined; and (d) the inactivation of activin signaling pathway was found to favor IPMN over PanIN development in vivo, which is interesting because the inactivation of SMAD4, a downstream target of both activin and TGFbeta signaling pathways, has been shown previously to favor the development of mucinous cystic lesions as well. The evidence suggests the potential importance of both activin and TGFbeta signaling pathways in the development of IPMN and MCN in humans.
Lessons Learned
Inactivation of a tumor-suppressor gene alone is insufficient to induce tumorigenesis in vivo. An oncogenic initiation, such as by mutant Kras, is essential. Good pathology support and good antibodies are very critical in mouse modeling projects. A shared database of workable antibodies for both human and mouse research would benefit the research community and reduce wasted efforts and resources.
Next Steps
A trove of tumor blocks and cell lines have been generated from the mouse model used in this study which will allow further study of any alterations (genetically and epigenetically) that may have occurred in activin signaling pathways as well in known oncogenic and tumor-suppressive pathways important to pancreatic tumorigenesis.
Follow-Up Funding
NIH/NCI R21 Grant (Start Date: 7/1/08). For continued study of the mouse model.
