Grant: Banting Postdoctoral Fellowship Program

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival of < 5%. Interestingly, these tumours contain a large stromal component that can comprise up to 90% of the tumour. Tumour-associated stroma provides a microenvironment to support tumour growth and progression, and has been shown to significantly hamper effective treatment of these cancers. The PDAC-associated stroma is hypothesized to derive from pancreatic stellate cells, which represent tissue resident mesenchymal stroma cells (MSCs). During our studies related to MSC biology, we have discovered a cellular program that appears to be important in regulating MSC activation and cell-cycle entry. The overall objective of this project is to better understand the functional role of this program involving two tumour suppressor proteins in pancreatic cancer progression and stroma. These two proteins are normally expressed in MSC/stellate cells within the pancreas, and their expression is decreased in activated MSCs. We hypothesize that deletion of either tumour suppressor protein in pancreatic stellate cells will create an environment conducive for PDAC development and progression. Our approach will utilize novel in vivo genetic models to manipulate expression of the tumour suppressor proteins. Collectively, this research plan will enable us to answer several questions regarding the contribution and fate of activated MSCs in the pancreas, enabling us to identify novel mechanisms for targeting the activated stroma in pancreatic cancer.