Novel model for studying PDAC using normal human pancreatic tissue For the past twenty years, the survival rate for many cancers has improved, but survival for pancreatic ductal adenocarcinoma (PDAC) has not, due to lack of both early detection methods and effective treatments. Human PADC cancer cell lines have been widely used. However, such cell lines are far from original organ tissue, and their highly unstable genome complicates interpretation. On the other hand, while animal models overcome many of the limitations of cell lines, genetically engineered mouse models (GEMMs) may overlook some profound differences between human and mouse cells. Indeed, nearly 90% of drugs with proven efficacy in animal models are ineffective in clinical trials. In our previous studies, we have successfully induced ADM in primary human normal acinar cells and found distinct features of human cells. We further engineered these acinar-derived ductal like (AD) cells to PDAC cells by specifically introducing the landscape mutation combination (KRAS/P16/TP53/SMAD4, KPTS) of human PDAC. Importantly, when transplanted into mice, these genetically engineered cells gave rise to invasive desmoplastic tumors, recapitulating the clinical features of PDAC in human patients, highlighting the power of this novel system to modeling human PDAC development. Given the fact that PDAC gains mutations during progression, we propose to use our novel system to generate engineered cells carrying fewer mutations, which may give rise to non-invasive neoplasia when orthotropically transplanted into NOD-SCID mice. This model will not only help us to understand the mechanisms of human PDAC development, it may also be a valuable platform to identify biomarkers for early diagnosis. Since our engineered AD cells give rise to tumors recapitulating clinical features of human PDAC, they are a good model to identify key targets to stop the growth of fully established tumors in vivo. To test this concept, we will utilize an inducible gRNA expressing vector to specifically knockout oncogenic KRAS in vivo to induce tumor size reduction. Success with this method would provide a powerful model to identify other essential genes supporting human PDAC progression and to reveal possible pathways for human PDAC relapse after KRAS knockout. The proposed novel models have great clinical potential on precision medicine, identification of early diagnosis methods, and development of new treatment strategies for human PDAC.
We propose to use normal human pancreatic tissue from a donor to develop a novel model system that we can use to investigate how pancreas cells first start becoming cancerous and how they progress to malignant cancer. Using human cells will allow us to examine human specific signals and pathways, and using normal cells will allow us to understand how pancreatic cancer starts and what signals promote cancer development. Our model will also provide a platform for developing tests for early pancreatic cancer diagnosis and more specific and effective treatments for this deadly disease.
|Akanuma, Naoki; Liu, Jun; Liou, Geou-Yarh et al. (2017) Paracrine Secretion of Transforming Growth Factor ? by Ductal Cells Promotes Acinar-to-Ductal Metaplasia in Cultured Human Exocrine Pancreas Tissues. Pancreas 46:1202-1207|