小柯机器人

美国斯隆·凯特琳纪念癌症中心 Scott W. Lowe课题组在研究中取得进展。他们研究发现基因-环境诱导的表观遗传重塑促进肿瘤发生。相关论文于2021年2月3日在线发表于国际学术期刊《自然》杂志。

通过整合基因组学、单细胞染色质分析和喂养小鼠时空调控功能扰动模型，研究人员发现Kras突变与组织损伤相结合诱发了胰腺上皮细胞独特的染色质状态，从而将赘生性转化与正常再生区分开来，并且选择性用于恶性进展。这种与癌症相关的表观遗传状态会在胰腺损伤后48小时内出现，并涉及“腺泡瘤形成”染色质转换，从而导致人胰腺癌基因的早期失调。

在恶性前胰腺上皮组织损伤过程中活化最快的因子是警报蛋白细胞因子白细胞介素33，这表明了损伤与Kras突变共同促进早期肿瘤形成以及对赘生性转化表观遗传重塑程序的影响。总的来说，该研究揭示了基因与环境之间的相互作用如何快速产生决定早期肿瘤发生的基因调控程序，并为理解癌症发生过程中遗传与环境因素之间的相互作用提供了分子模型。

据了解，组织损伤通过未知机制增加了癌症的发病风险。在小鼠胰腺癌模型中，组织损伤造成的胰腺炎与致癌基因Kras激活突变协同作用，显著加速了早期肿瘤性病变的形成，并最终促进腺癌的发生。

附：英文原文

Title: A gene–environment-induced epigenetic program initiates tumorigenesis

Author: Direna Alonso-Curbelo, Yu-Jui Ho, Cassandra Burdziak, Jesper L. V. Maag, 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 Mazutis, Steven D. Leach, Richard Koche, Dana Peer, Scott W. Lowe

Issue&Volume: 2021-02-03

Abstract: 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.

DOI: 10.1038/s41586-020-03147-x

Source: https://www.nature.com/articles/s41586-020-03147-x

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