Regulation of lineage plasticity in pancreatic disease by the pioneer factor FOXA2

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

PROJECT SUMMARY During pancreatitis, acinar cells undergo a cell fate change, known as acinar-to-ductal metaplasia (ADM). The metaplastic response can be viewed as an adaptive phenomenon, functioning to limit tissue damage through the transient loss of the acinar cell fate and repression of digestive enzyme production. However, pancreatitis is a major risk factor for the development of many pancreatic diseases. The inherent plasticity of the acinar cell creates a susceptibility to permanent acinar-to-ductal reprogramming, contributing to the formation of pancreatic neoplasia. Despite pancreatitis being a well-known source of morbidity, we do not understand the precise mechanisms governing this cell state transition. Thus, it is critical to study how acinar cell plasticity is regulated in the context of tissue injury. This will enable the identification of molecular dependencies of pancreatitis, offering new opportunities to intervene during the early disruption of pancreatic homeostasis. To understand how acinar cell plasticity is regulated, I first compared the transcriptional and chromatin accessibility landscapes of acinar, ductal, progenitor, and metaplastic cells with bulk RNA-seq and ATAC-seq. ADM has historically been described as a transdifferentiation of mature acinar cells into a “duct-like” state. My preliminary evidence suggests that ADM is a complex cell state, featuring the dedifferentiation of acinar cells to a late progenitor phenotype. Motifs belonging to the Forkhead box (Fox) family transcription factor FOXA2 were made highly accessible during ADM. FOXA2 is a pioneer factor with well-studied roles in pancreatic development, yet its contribution to adult acinar cell homeostasis is underexplored. In preliminary experiments using in vivo models of pancreatitis and conditional knockout, I have observed that FOXA2 is required for the metaplastic response to injury. Therefore, I hypothesized that FOXA2 controls acinar cell plasticity by directing the acquisition of a progenitor-like state during pancreatitis and supports eventual neoplasia by facilitating acinar- to-ductal reprogramming. I will utilize transcriptomic and epigenomic approaches to delineate how FOXA2 functions to direct lineage plasticity during pancreatitis. With in vitro and in vivo models, I will assess if FOXA2 contributes to the initiation of pancreatic neoplasia by determining if FOXA2 is required for permanent acinar-to-ductal reprogramming. Crucially, the proposed investigations will enhance my training and growth as a scientist. I will become familiar with sophisticated in vivo and in vitro models and will be exposed to cutting-edge epigenomic investigations that will help to build a strong foundation for my future career as an independent investigator.