GSE132326
An epigenetic program established by gene – environment interactions initiates pancreatic carcinogenesis  [Set1]
Damaged tissues have increased risk of cancer development through poorly understood mechanisms. In the pancreas, tissue damage collaborates with activating mutations in the Kras oncogene to dramatically accelerate the formation of early neoplastic lesions and ultimately pancreatic cancer. By integrating genomics, single-cell chromatin assays and spatiotemporally-controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves large-scale chromatin accessibility changes that contribute to the early dysregulation of genes defining human pancreatic cancer. Among the genes most rapidly activated by tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine IL33, which cooperates with mutant Kras in unleashing the epigenetic remodeling program of early neoplasia and neoplastic transformation in the absence of injury. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene regulatory programs that dictate early neoplastic commitment and provides a molecular framework for understanding the interplay between genetics and environmental cues in cancer initiation. Overall design: Characterization of the transcriptional profiles of bulk lineage-traced pancreatic epithelial cells isolated directly by FACS-sorting (mKate2+ or GFP+) from normal, regenerating, early neoplastic and malignant murine pancreatic tissues: To compare the effects of tissue injury in mutant Kras-expressing or Kras wild-type pancreatic epithelial cells, cells were sorted from KC;RIK (p48-Cre;RIK;LSLKrasG12D) or C;RIK (p48-Cre;RIK) male mice treated with caerulein or PBS (vehicle control) at 5 weeks of age, using littermates when possibe. To characterize invasive disease, pancreatic ductal adenocarcinoma (PDAC) cells were isolated from cancer lesions arising in autochthonous transgenic models (KPflC;RIK (p48Cre;RIK;LSL-KrasG12D;p53fl/+). 3-6 biological replicates (independent mice) were used per experimental condition.