Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human cancers. Although a recurrent set of gene mutations has been identified in this cancer type, this information has not translated into significant improvements in patient outcome. Our laboratory focuses on understanding the genetic program for PDAC initiation and progression. We have generated a series of genetically engineered mouse models and primary pancreatic cell culture systems for these studies. Our specific projects include:
Defining the originating stages of pancreatic cancer. Our preliminary results indicate that the Notch and Stat3 signaling may regulate the earliest stages of pancreatic cancer progression and may be required for maintenance of established tumors. We have generated engineered mouse strains that enable study of the role of Notch and Stat3 signaling throughout the course of pancreatic cancer progression. We are testing whether Notch and Stat3 signaling both defines the PDAC cell-of-origin and whether ongoing Notch activity is required for pancreatic cancer initiation and progression.
Understanding the role of Smad4/transforming growth factor-β (TGFβ) signaling in pancreatic cancer pathogenesis.
The TGFβ pathway appears to play dual roles in pancreatic ductal adenocarcinoma (PDAC) pathogenesis; restraining the early stages of tumor development while promoting the growth of advanced cancers. We are using inducible mouse models and primary cell systems to a) define the mechanisms by which Smad4 regulates progression of PDAC precursor lesions (PanINs) and b) to establish the molecular and cellular basis for TGFβ dependent promotion of advanced disease.
Defining the tumor suppressor function of Lkb1.
Lkb1 encodes a serine-threonine kinase implicated in the control of cellular energy metabolism and cell polarity. Individuals with germline Lkb1 mutations have a greatly increased incidence of pancreatic cancer. We are using genetic approaches to investigate the mechanisms by which Lkb1 loss initiates pancreatic cancer.
Identification of pancreatic cancer biomarkers.
There is currently no diagnostic test for early detection of pancreatic cancer. We have exploited the genetic homogeneity of the mouse model of pancreatic cancer in serum proteomics studies that have resulted in the identification of biomarkers relevant to the detection of the human disease. In a separate proteomics study we have used phage display to develop highly specific imaging probes to detect evolving pancreatic cancer. With respect to both of these studies, we are further validating these markers and seeking additional biomarkers specific to the genetic status of the tumors and that gauge treatment response.
Center for Cancer Research 