Early embryogenesis requires cell fate decisions that define the body axes and establish progenitor cell pools. However, development does not cease once lineages are specified. Instead, cells continue to undergo specific maturation events where changes in their transcriptome ensure that essential gene products are available to carry out unique physiological functions. For example, secretory pancreatic acinar cells mature post-natally to handle an extensive protein synthetic load, to establish an organized cell polarity and to orchestrate efficient cell-cell communication. One transcriptional effector that has been implicated in regulating these maturation events is MIST1, a secretory cell-restricted transcription factor. Mist1 deficient acinar cells fail to establish an apical-basal organization, fail to properly position zymogen granules, and fail to generate intercellular communication, making the injured exocrine organ highly susceptible to pancreatic disease. In an effort to test whether MIST1 directly induces and maintains the mature acinar cell phenotype, Cre-mediated Mist1 gene expression was activated in adult Mist1 deficient mice. Induction of Mist1 rapidly restored wildtype acinar gene expression patterns and produced dramatic changes in cellular phenotypes, including the generation of apical-basal polarity, increased zymogen granule size, reorganization of the actin cytoskeletal network, restoration of intercellular communication and recovery of regulated exocytosis function. These studies provide direct evidence that the injured adult exocrine pancreas can be remodeled in vivo and that MIST1 actively controls maturation processes, opening new therapeutic avenues for repairing damaged organs prior to developing pancreatic disease. Indeed, forced expression of Mist1 in a KrasG12D -induced mouse model of pancreatic carcinogenesis suppressed pre-cancerous lesion formation as well as the accompanying stromal response. These results suggest that maintaining MIST1 activity in KrasG12D-expressing acinar cells can partially mitigate the transformation activity of oncogenic KRAS. Future therapeutics that target Mist1 transcriptional networks may show promising efficacy in combating pancreatic cancer.
|Advisor:||Konieczny, Stephen F.|
|Commitee:||Fekete, Donna M., Mendrysa, Susan M., Szeto, Daniel|
|School Location:||United States -- Indiana|
|Source:||DAI-B 74/03(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Cellular biology, Developmental biology, Oncology|
|Keywords:||Acinar cell homeostasis, Carcinogenesis, Exocrine, Mist1, Pancreas, Panin, Secretory, Transcription|
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