Abstract A05: Chromatin dynamics in vivo reveal a complex cell fate transition and master regulators of the development of pancreatic intraepithelial neoplasia
Authors: Chandwani Rohit , Osterhoudt Alexa , Koche Richard , Leach Steven D. 
Published: March 2020

Abstract
Pancreatic cancer initiation features a hallmark preneoplastic event wherein the acinar cell acquires a “duct-like” phenotype. Despite this transition in cell fate, little is known about the chromatin specification of pancreatic cell types and the epigenetic dysregulation of normal acinar cells in tumor initiation. To address these questions, we employed a lineage-traced autochthonous mouse model (Mist1-CreERT2 LSL-TdTomato +/- LSL-KrasG12D) to examine systematically perturbed acinar cells that give rise to early PanIN (PanIN 1); in addition, we sorted islet and ductal cell populations and describe the novel generation of Ptf1a-TdTomato mice to reliably sort pancreatic progenitors at e10.5. We observe in our system that Kras activation alone does not disturb acinar cell chromatin nor the histologic appearance of the pancreas. By contrast, caerulein alters chromatin significantly in metaplasia and even in regeneration, with putative enhancers derepressed despite normal histology. In the context of Kras activation and caerulein administration, we find a broad and stable reorganization of chromatin, reflecting cooperativity between oncogenic stress and an inflammatory insult. The chromatin of the reprogrammed acinar cell bears few, if any, ductal, progenitor, or islet features and instead reflects a largely novel cell fate. Detailed analysis of these acinar-derived cells in PanIN1 reveals unexpected features of the newly acquired cell state. First, we find robust induction of epithelial-mesenchymal transition (EMT) gene-proximal enhancer chromatin that is not reflected in the EMT-related transcriptional state. Second, we find evidence of a derepression of a foregut/gastric transcriptional program, not otherwise evident in normal cell types of the adult mouse pancreas. Finally, our genome-wide chromatin accessibility and transcriptome data nominate the pioneer transcription factor Foxa1 as a master regulator of the complex cell fate transition from acinar cell to PanIN. Together, our findings suggest that (1) the acquired acinar cell fate reflects neither true metaplasia nor transdifferentiation nor dedifferentiation events, (2) a gastric/foregut transcript program is unveiled, (3) the process of EMT begins in ADM, and finally (4) that Foxa1 appears to coordinate the change in cell fate. Our data thus demonstrate that histologic appearance does not adequately reflect cellular identity, highlighting the complex spectrum of features acquired in the transition to neoplasia and identifying a putative coordinator of the PanIN cell fate.
Citation Format: Rohit Chandwani, Alexa Osterhoudt, Richard Koche, Steven D. Leach. Chromatin dynamics in vivo reveal a complex cell fate transition and master regulators of the development of pancreatic intraepithelial neoplasia [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A05.