Sunday, May 11, 2025
5/11/2025
Mechanisms of injury-induced pancreatic neoplasia - Pancreatitis is a major gastrointestinal disorder for which there is no effective treatment. In response to injury, pancreatic acinar cells undergo transient transdifferentiation called acinar-to-ductal metaplasia (ADM). This process allows the tissue to recover from insult. Upon resolution of the injury, the transdifferentiated cells revert to acinar cells. If, however, upon repeated injuries the regenerative mechanisms fail, the tissue may sustain irreversible damage, often resulting in multifocal pancreatic intraepithelial neoplasia (mPanIN) and eventually cancer. Pancreatic stellate cells (PSCs) play a pivotal role in the acinar cells’ replacement by fibrotic tissue and in a combination with chronic inflammatory conditions expedite the development of pancreatic cancer. Thus, it is important to understand the mechanisms that govern ADM and mPanIN formation and to identify factors that can be used to prevent or alleviate this undesirable cellular transformation. Krüppel-like factor 5 (KLF5) is a member of the zinc finger family of transcription factors and is important in regulating key cellular functions including proliferation, differentiation, and migration. We and others have shown that KLF5 is highly expressed in human pancreatic cancer-derived cell lines and primary pancreatic cancer tissues. Using mouse models, we showed that KLF5 promotes the survival of pancreatic cancer cells and that depleting KLF5 in pancreatic cancer cells disrupts their ductal phenotype and reduces their proliferation in vitro and in vivo. Notably, our preliminary results from mouse cerulein- and KRAS-induced injury models demonstrate that KLF5 is both necessary and sufficient for the step-wise progression from acinar cells to ADM to mPanIN. Furthermore, we showed that N-myc downstream-regulated gene 2 (NDRG2), a known tumor suppressor, is a molecular target of KLF5 and the KLF5-NDRG2 axis may regulate the pancreas’ response to injury and transformation. The Long-Term Goal of this research proposal is to elucidate the mechanisms regulating transformation of pancreatic acinar cells upon chronic injury. Based on our novel and exciting findings, our Central Hypothesis is that KLF5 acts as a critical mediator of the injury response program and is essential for ADM development and progression toward mPanIN. To test this hypothesis, we propose three Specific Aims: 1) to investigate the role of KLF5 in modulating the tissue microenvironment during chronic pancreatitis, 2) to determine whether NDRG2 (a KLF5 molecular target) functions downstream of KRAS and KLF5 during formation of ADM and progression toward mPanIN, and 3) to evaluate a targeted approach for prevention, maintenance, and progression of pancreatic neoplasia. Taken together, the experiments proposed in this application will provide definitive information on how KLF5 regulates the early stages of pancreatic neoplasia and will allow efficacy assessment of small molecule KLF5 inhibitors for the prevention and progression of chronic pancreatitis. Furthermore, understanding the processes regulating acinar cell plasticity, and the role KLF5 plays therein, will help to identify markers for early disease detection, and therapeutic targets for mitigating progression of pancreatic disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).