Project 1: Elucidating the genetics and cell of origin of pancreatic cancer initiation

点击翻译按钮获取中文摘要

ABSTRACT (Project 1) Pancreatic ductal adenocarcinoma (PDAC) is a prevalent and almost uniformly fatal malignancy. Human PDAC genome sequencing has identified recurrent mutations in Kras and several major tumor suppressor genes (TSGs), but the impact of these alterations in the initiation and evolution of human PDAC development remain poorly understood at the molecular level. Understanding the basis of tumor initiation and development has critical implications for improving early diagnosis and therapy. While PDACs were originally thought to arise from ductal cells, evidence from mouse models suggests that acinar cells can give rise to PDACs through a regenerative, transdifferentiation process known as Acinar to Ductal Metaplasia (ADM). ADM is stimulated by chronic pancreatitis, a known risk factor for PDAC, and generates premalignant Pancreatic Intraepithelial Neoplasias (PanINs), which lead to PDAC. Our preliminary data suggest that the p53 TSG can inhibit ADM and that p53 inactivation in acinar cells expressing oncogenic KrasG12D drives PDAC. However, expression of oncogenic KrasG12D and p53 inactivation in ductal cells can also induce PDAC, suggesting alternate routes of PDAC carcinogenesis. Interestingly, we find that acinar cell-derived and ductal cell-derived tumors resemble the classical and basal-like subtypes of human PDAC, respectively. These results underscore the unique value of mouse models in uncovering the determinants that dictate different paths of PDAC evolution to provide insight into human PDAC. The roles of other common PDAC TSGs in early stage pre-neoplastic lesions, including whether they normally function in acinar cells and/or ductal cells, however, remains unclear. Furthermore, oncogenic Kras mutations are diverse in PDAC, yet it is unknown whether different mutations have distinct impacts on PDAC development from different pancreatic epithelial cell types. We hypothesize that the cell type of origin and tumor genotype cooperate to drive different paths of PDAC development, and to test this idea, we will systematically inactivate several major PDAC TSGs and express different Kras alleles in both putative cell types of origin. We will characterize the transcriptomes and the cellular milieu of early lesions and tumors and employ innovative approaches like somatic genome editing and molecular barcoding. We will compare our studies in tractable mouse models to studies of human PDAC development. Together, these transformative studies will establish how genetic determinants and cell-of-origin influence the molecular pathways and the cellular microenvironment during PDAC evolution in mice and humans, critical knowledge for better clinical management of this deadly disease.