Tissue damage increases the risk of cancer through poorly understood mechanisms¹. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma^2,3. Here, 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 an ‘acinar-to-neoplasia’ chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. 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 genetic and environmental cues in the initiation of cancer.

组织损伤通过鲜为人知的机制增加患癌症的风险¹。在小鼠胰腺癌模型中，与组织损伤相关的胰腺炎与Kras癌基因的激活突变协同作用，显着加速早期肿瘤病变的形成，并最终形成腺癌^2​​,3。在这里，通过在本地小鼠模型中整合基因组学、单细胞染色质测定和时空控制的功能扰动，我们发现Kras突变和组织损伤的结合促进了胰腺上皮中独特的染色质状态，这种状态将肿瘤转化与正常再生区分开来，并且是选择用于整个恶性进化。这种与癌症相关的表观遗传状态在胰腺损伤后 48 小时内出现，并涉及“腺泡到肿瘤”染色质转换，导致人类胰腺癌基因的早期失调。癌前胰腺上皮组织损伤后最快速激活的因子之一是警报素细胞因子白细胞介素 33，它概括了损伤与突变体Kras合作释放早期肿瘤和肿瘤转化的表观遗传重塑程序的影响。总的来说，我们的研究证明了基因与环境的相互作用如何快速产生决定早期肿瘤形成的基因调控程序，并为理解癌症发生过程中遗传和环境线索之间的相互作用提供了分子框架。