A lineage-specific epigenetic memory of inflammation potentiates Kras-driven pancreatic tumorigenesis

Tissue homeostasis depends on responses to environmental insults to restore cellular phenotype, microenvironment composition, and tissue architecture. Inflammation is essential to the disruption of homeostasis in epithelial tumorigenesis, but how a temporally remote inflammatory episode impacts tumor development is unknown. Herein we employ lineage-traced mouse models to unveil the presence of an epigenetic memory of inflammation. We observe that despite histologic resolution of pancreatitis, acinar cells fail to return to the same molecular baseline. In vivo, the memory is associated with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis when instead subjected to an oncogenic Kras mutation. We find that memory is a cell-intrinsic property, primarily encoded in chromatin, that features persistent derepression of metaplastic genes and is recalled with oncogenic stress. Together, our findings define a capacity for an environmental insult to potentiate future tumor initiation, broadening the relationship between inflammation and cancer.