| Description |
Pancreatic ductal adenocarcinoma is a highly lethal human cancer that originates from acinar cells in the pancreas. Ptf1a is a transcription factor that plays an important role in the development of the pancreas and in the differentiation and maintenance of acinar cells. Ptf1a expression is lost during cancer formation, and deletion of Ptf1a in a mouse model of pancreatic cancer results in accelerated cancer progression. In addition, induced expression of Ptf1a in precancerous cells can reprogram them back to normal acinar cells. However, when Ptf1a is expressed alone in fibroblast cells, it is not able to work as a master regulator transcription factor to reprogram fibroblasts into acinar cells. This thesis presents an experiment testing whether Ptf1a needs additional acinar specific transcription factors in order to reprogram fibroblast cells into acinar cells. Our findings show that different acinar transcription factors are required alongside Ptf1a in order to promote expression of different acinar target genes. Combinations with multiple acinar transcription factors tend to be the most successful at inducing expression of target genes. Although multiple acinar-specific target genes were induced, their expression did not reach the levels of normal acinar cells. More research using different transcription factor combinations, chromatin opening drugs, and specifying order of expression may allow us to successfully reprogram fibroblasts to an acinar identity. Our future research hopes to illuminate how Ptf1a works with other acinar transcription factors to establish and maintain acinar cell identity, and potential mechanisms by which this might restrict the formation of pancreatic cancer. |
