Pancreatic ductal adenocarcinoma (PDA) is the 3rd most common cause of cancer-related death in the United States. This dismal outcome is in part due to the lack of understanding of the unique pathology of PDA that includes pronounced epithelial plasticity and evolution of an extensive reactive fibroinflammatory stroma. We have discovered an unusual cell type within preneoplasia and neoplasia known as the metaplastic tuft cell (MTC), which has been proposed to act as both a tumor initiating cell and as a chemosensory cell that drives the fibroinflammatory host response. Normal tuft cells are found in normal glandular tissues and are marked by the expression of the microtubule kinase DCLK1. There they sample the luminal environment and respond to signals by modifying the Type 2 immune response. While there are no tuft cells found in the normal pancreas, they arise in a transdifferentiation event to become part of the metaplastic and neoplastic epithelium during oncogenesis or tissue injury. Besides their chemosensory function, they have been hypothesized to be a tumor initiating progenitor cell. In order to definitively determine the origins and functions of the metaplastic tuft cell, we have created a dual recombinase driven mouse model of pancreatic neoplasia combined with an inducible Cre recombinase that specifically targets MTCs that will allow us to alternatively trace and target the metaplastic tuft cells independent of neoplastic transformation in vivo. We have also devised human and mouse organoid culture systems that preserve tuft cell differentiation, so that we can study their genesis, fate and chemosensory function in more detail. Together, these tools will be used to rigorously determine the function of the metaplastic tuft cell and whether manipulating their functions can be used to treat pancreatic cancer.
Pancreatic cancer is almost universally fatal. We previously identified the DCLK1-expressing metaplastic tuft cell in metaplastic and neoplastic lesions early in disease progression where they are hypothesized to act as tumor progenitor cells, but also have a chemosensory function that they utilize to modify the fibroinflammatory response. In this proposal, novel genetic models will be employed to explore the origin and definitively determine the functions of the metaplastic tuft cell in pancreatic cancer.
