Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
J Exp Med. 2021 Jun 7;218(6). doi: 10.1084/jem.20200219.
Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.
胃癌（GC）是世界上最常见的致命癌症之一。尽管患者基因组数据已经确定 AT 丰富相互作用域 1A（ARID1A）是仅次于 TP53 的第二个最常突变基因，但它在胃癌发生中的体内作用及其与 TP53 的关系仍不清楚。我们建立了一种新型的小鼠模型，反映了大多数人类 GC 病例中发现的 ARID1A 杂合突变，该模型表明 ARID1A 杂合性通过全局丧失增强子并随后抑制 p53 和细胞凋亡途径促进肿瘤进展。此外，小鼠遗传和单细胞分析表明，通过激活 p53 途径，Arid1a 的纯合缺失赋予了竞争劣势，突出了其不同的剂量依赖性作用。利用 ARID1A 突变 GC 细胞的这种独特脆弱性，我们联合使用表观遗传抑制剂 TP064 和 p53 激动剂 Nutlin-3，抑制了 ARID1A 杂合肿瘤类器官的生长，为 GC 提供了一种新的治疗选择。
