Grant: Project Grant

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival of < 5%. Interestingly, these tumours contain a large stromal component that can comprise up to 90% of the tumour. The tumour-associated stroma provides a microenvironment to support tumour growth and progression, and has been shown to significantly hamper effective treatment of these cancers. It has been shown that the stroma may have some protective benefits, therefore complete stromal depletion may be detrimental. There is a need to identify whether more specific stromal depletion or modulation methods are possible, with the goal of improving drug delivery and improving patient survival. The PDAC-associated stroma is hypothesized to derive from pancreatic stellate cells (PSCs), which represent tissue resident mesenchymal stromal cells (MSCs). During our studies related to PSC biology, we have discovered a cellular program that appears to be important in regulating PSC activation and cell-cycle entry. The overall objective of this project is to utilize novel mouse models to identify key genes expressed in the tumour stroma- specifically in the PSCs. Novel therapeutic targets will be validated in a large cohort of well-annotated patient specimens, and druggable targets will be prioritized utilizing in vitro culture systems and a collection of patient-derived mouse models (xenografts). Collectively, this research plan will allow us to answer several questions regarding the contribution and fate of activated PSCs in the pancreas, and will enable us to identify novel mechanisms and rational therapeutic combinations for modulating the activated stroma in pancreatic cancer.