Grant: CIHR New Investigator

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in Canada. This cancer has been called a "silent killer" because it often does not cause symptoms until very late stages of the disease. At this point, treatment options are limited because the tumor is very resistant to chemotherapy and surgery is often not an option. There are, however, documented cases of patients responding exceptionally well to therapy. This variable therapeutic response emphasizes that there are differences between tumors, which is also known as heterogeneity. Pancreatic cancer heterogeneity has also been observed through differential expression of genes between tumors, but it is unclear what molecular or cellular mechanisms underlie the development of this variability. To improve disease outcomes, we need to better understand what causes this heterogeneity so that we can identify diagnostic tools to robustly identify tumor subtypes. If we can identify tumor subtypes, we can then develop effective treatments against those subsets. To begin to understand heterogeneity, we will use animal models to manipulate characteristics underlying tumor initiation and examine their impact on tumor heterogeneity. Briefly, we will examine whether combinations of different initiating cell types or gene mutations result in differences in tumor appearance, gene expression, or the type of additional mutations present in the tumor. We will then determine whether key differences identified in our models identify subsets of human tumors with distinct clinical outcomes. These studies will expand our understanding of factors underlying the development of tumor heterogeneity and also provide preclinical models to test novel therapeutic strategies potentially revealed by our studies. The knowledge generated by this research will aid identification of molecular markers that can reproducibly identify human PDAC subtypes with distinct therapeutic responses and clinical outcomes.