UCSF

Diseases of the pancreas affect a large portion of the world's population; pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer deaths and type 2 diabetes is now reaching epidemic levels. Mouse models of pancreatic diseases have been instrumental in defining our understanding of the initiation and progression of these diseases. My studies examined various aspects of proper function of pancreatic cells and the development of disease, including the role of Numb in regulation of acinar cell dedifferentiation and metaplasia, and the role of stromal changes in the development of both PDA and regulation of glucose homeostasis.

Studies of mouse models of PDA have indicated that the most common cell type in the pancreas, the acinar cell is capable of giving rise to precursor lesions and PDA under the direction of activated Kras. However, even when Kras is activated in a majority of acinar cells, only a small percentage of cells go on to result in precursor lesions and disease in the absence of additional stresses such as additional mutations and/or inflammation. Here I demonstrate that Numb, a protein with a multitude of functions in regulation of signaling pathways, cell junction formation, endocytosis and asymmetric division, restrains acinar cell dedifferentiation and acinar to ductal metaplasia and promotes cell viability.

In addition to cell intrinsic changes, alterations in the stromal microenvironment are well documented in pancreatic disease. Specifically, changes in inflammatory cells have been well documented in PDA development, but how these different cell types influence PDA development is unclear. My work reveals that neutrophils are important for propagating pancreatic damage and acinar dedifferentiation, but are not instrumental in the formation of initiating lesions that lead to PDA development.

Finally, the pancreatic mesenchyme is critical for pancreatic development, but how these cells contribute to tissue homeostasis is unknown. My studies demonstrate that pancreatic mesenchymal cells are found throughout the adult pancreas and that they are essential for maintenance of acinar cell organization and glucose homeostasis, partially through regulation of the extracellular matrix.