克拉斯
表观遗传学
肿瘤转化
胰腺癌
癌变
生物
癌症研究
染色质
胰腺上皮内瘤变
癌症
恶性转化
染色质重塑
基因
遗传学
细胞生物学
结直肠癌
作者
Direna Alonso-Curbelo,Yu-Jui Ho,Cassandra Burdziak,Jesper L.V. Mååg,John P. Morris,Rohit Chandwani,Hsuan-An Chen,Kaloyan M. Tsanov,Francisco M. Barriga,Wei Luan,Nilgun Tasdemir,Geulah Livshits,Elham Azizi,Jaeyoung Chun,John E. Wilkinson,Linas Mažutis,Steven D. Leach,Richard P. Koche,Dana Pe’er,Scott W. Lowe
出处
期刊:Nature
[Springer Nature]
日期:2021-02-03
卷期号:590 (7847): 642-648
被引量:131
标识
DOI:10.1038/s41586-020-03147-x
摘要
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, adenocarcinoma2,3. 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. In mouse models of pancreatic cancer, a cooperative interaction between tissue damage and Kras gene mutation rapidly induces cancer-associated chromatin states in pre-malignant tissue, leading to gene dysregulation and neoplastic transformation.
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