Investigating the role of the basic helix-loop-helix transcription factor MIST1 in pancreatic diseases

Acinar cells of the exocrine pancreas are dedicated to synthesize, package and secrete immense quantities of pro-digestive enzymes to maintain proper metabolic homeostasis for the organism. Dysregulation of enzyme secretion in acinar cells can give rise to exocrine diseases including acute pancreatitis (AP), a disease that targets acinar cells, leading to acinar-ductal metaplasia (ADM), inflammation and fibrosis—events that can transition into the earliest stages of pancreatic ductal adenocarcinoma (PDAC). The focus of this thesis is to interrogate transcriptional regulatory networks that are susceptible to AP and the role that these networks play in acinar cell and exocrine pancreas responses. The overall goal is to determine the importance of the acinar-specific maturation transcription factor MIST1 to AP damage and organ recovery and its role in AP induced PDAC upon oncogenic transformation. Analysis of wild-type and Mist1 conditional null mice revealed that Mist1 gene transcription and protein accumulation are dramatically reduced as acinar cells undergo ADM alterations during AP episodes. To test if loss of MIST1 function is primarily responsible for the damaged status of the organ, mice harboring a Cre-inducible Mist1 transgene (iMist1) were utilized to determine if sustained MIST1 activity could alleviate AP damage responses. Surprisingly, constitutive iMist1 expression during AP produced a dramatic increase in organ damage followed by acinar cell death. This result suggests that the transient silencing of Mist1 expression is critical for acinar cells to survive an AP episode, providing cells an opportunity to suppress their secretory function and regenerate damaged cells. In order to further define the role of MIST1 in pancreatic neoplasia lesion formation (a precursor of PDAC), Mist1 conditional null mice were generated that contained a mutated oncogenic KrasG12D allele. Direct comparison between embryonic Mist1 null mice with conditional Mist1 null mice in the context of KRASG12D activity demonstrated that embryonic Mist1 null mice are more susceptible to PanIN formation. The importance of MIST1 to these events suggests that modulating key pancreas transcription networks could ease clinical symptoms in patients diagnosed with pancreatitis and pancreatic cancer