My primary research interests include designing, generating, and using transgenic mouse models of pancreatic cancer in order to understand disease etiology and mechanisms that can detect or circumvent these processes. Our primary research interests include designing, generating, and using mouse models of pancreatic cancer in order to understand: (1) a means of early detection, (2) disease etiology and causative mechanisms, and (3) chemopreventive and/or therapeutic strategies.
One such model that was generated from previous work includes the EL-KrasG12D transgenic mouse. These mice develop mutant Kras-induced pancreatic ductal carcinoma in situ (dCIS), which are similar to human neoplastic lesions (PanIN, IPMN, & MCN). EL-Kras mice have been instrumental in identifying aspects related to our research goals, which have been further strengthened by the Pdx1-Cre/LSL-Kras mouse model. In addition, our laboratory employs pancreatic cancer and human pancreatic ductal epithelial cell lines as model systems to both explore mechanisms involved in pancreatic carcinogenesis and correlate these findings with both mouse and human tissue. Our ultimate goal is to define novel mechanisms related to recently identified pathways and exploit these systems for earlier detection and treatment. This, in effect, bridges all of our goals.
Employing these engineered mouse models of pancreatic cancer and cell culture systems, I have pursued several projects regarding the cellular and molecular mechanisms of early stages of pancreatic carcinogenesis. Most of these projects are related to identifying causative genetic components above and beyond a mutation in Kras including loss of PEDF, Tgfbr1 haploinsufficiency, or altered expression of Cox-2 and/or 5-Lox. Other projects focus on oncogene addiction, early detection strategies (MRI and proteomics), and chemoprevention (evaluating the effects of high PUFA diets on mutant Kras-induced pancreatic precancer). Future work aims at assessing novel therapies using these and other genetically modified mice.
Beyond these current models, several other efforts employ tetracycline inducible and cre-lox recombination systems in attempts to generate regulated expression of oncogenes and tumor suppressor genes while targeting several pancreatic cell types. Inducible expression of mutant Kras targeted to elastase, pdx1, and nestin-positive cells is currently being evaluated in mice. The functionality of the tetracycline inducible system was previously demonstrated. Having multiple cell types to target in the pancreas will address which cell type(s) are reasonable candidates for the initiation and progression of pancreatic cancer.
The ramifications of all this work includes the design and implementation of mouse models of pancreatic cancer for evaluation of early detection modalities with clinical value, understanding the role of altered gene expression and diet during early stages of pancreatic cancer, and identifying novel targets and more efficacious therapies in these preclinical systems.