Abstract PR009: An epigenetic memory of inflammation controls context-dependent lineage plasticity in the pancreas

Abstract

Abstract Inflammation is essential to the disruption of tissue homeostasis, and, in the pancreas, can destabilize the identity of terminally differentiated acinar cells. A longstanding question has been whether a history of past injuries instructs subsequent homeostatic responses to future stimuli – despite being distantly separated in time. Thus, we employ here Mist1-CreERT2; LSL-tdTomato lineage-tracing mice to investigate the long-term effects of a transient inflammatory episode on pancreatic tissue homeostasis. We delineate the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and reveal that the pancreatic acinar cell compartment durably retains specific inflammation-induced epigenetic changes even 18-weeks after exposure to the original inflammatory stimulus. We observe that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular baseline after several months, representing an incomplete cell fate decision. Motif analysis demonstrates the enrichment of AP-1/Fra1 motifs at these persistently accessible memory regions—a transcriptional effector activated downstream of the Ras/MAPK pathway. This epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis with an oncogenic Kras mutation. We demonstrate that pancreatic acinar cells exhibit rapid malignant transformation upon re-challenge with oncogenic stress via inflammatory memory recall, with robust reactivation of genes associated with differentially accessible memory regions. Together, our findings define the dynamics and recall of an epigenetic memory of inflammation that impacts cell fate decisions in a context-dependent manner. Citation Format: David J. Falvo, Adrien Grimont, Paul Zumbo, Julie L. Yang, Alexa Osterhoudt, Grace Pan, Andre F. Rendeiro, John E. Wilkinson, Friederike Dündar, Olivier Elemento, Rhonda K. Yantiss, Doron Betel, Richard Koch, Rohit Chandwani. An epigenetic memory of inflammation controls context-dependent lineage plasticity in the pancreas [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR009.