Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Uncovering mechanisms responsible for the heterogeneous clinical features of this disease is an essential step toward developing improved and more specific therapeutic approaches. Here, we sought to identify transcriptional regulators of aggressive PDAC growth through in vivo CRISPR screening of epigenetic and transcription factors in an orthotopic model. We identified the ISL LIM homeobox 2 (ISL2) gene as a tumor suppressor whose depletion enhances the proliferation of human PDAC cells in vitro and in vivo and cooperates with activated KRAS to initiate PDAC in a murine model. Conversely, the upregulation of ISL2 expression through CRISPR-mediated locus-specific epigenetic editing results in reduced cell proliferation. Importantly, ISL2 is epigenetically silenced through DNA methylation in ~60% of PDAC tumors, which correlates with poor patient outcome. Functional studies showed that ISL2 loss rewires metabolic gene expression, and consequently potentiates oxidative phosphorylation while reducing glycolysis. This metabolic shift creates selective vulnerability to small molecule inhibitors of mitochondrial respiration and fatty acid oxidation. Collectively, these findings reveal ISL2 as a novel tumor suppressor whose inactivation drives metabolic reprogramming in an aggressive PDAC subset and point to potential therapeutic vulnerabilities in these tumors.

中文翻译：

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ISL2是表观遗传学上沉默的肿瘤抑制因子和胰腺癌的代谢调节剂

胰腺导管腺癌（PDAC）仍然是最致命的癌症之一。揭示造成这种疾病异质性临床特征的机制是开发改进的和更具体的治疗方法的重要步骤。在这里，我们试图通过在原位模型中对表观遗传和转录因子进行体内CRISPR筛选来鉴定侵袭性PDAC生长的转录调节因子。我们确定ISL LIM同源框2（ISL2）基因为肿瘤抑制因子，其耗竭作用可在体外和体内增强人类PDAC细胞的增殖，并与激活的KRAS协同在鼠模型中启动PDAC。相反，通过CRISPR介导的基因座特异性表观遗传编辑对ISL2表达的上调导致细胞增殖减少。重要的，ISL2在约60％的PDAC肿瘤中通过DNA甲基化在表观遗传上沉默，这与患者预后不良相关。功能研究表明，ISL2丢失使新陈代谢基因表达重新排列，因此增强了氧化磷酸化，同时减少了糖酵解。这种代谢变化对线粒体呼吸和脂肪酸氧化的小分子抑制剂产生选择性脆弱性。总的来说，这些发现揭示了ISL2作为一种新型的肿瘤抑制因子，其失活驱动了侵略性PDAC亚群中的代谢重编程，并指出了这些肿瘤的潜在治疗脆弱性。因此增强了氧化磷酸化，同时减少了糖酵解。这种代谢变化对线粒体呼吸和脂肪酸氧化的小分子抑制剂产生选择性脆弱性。总的来说，这些发现揭示了ISL2作为一种新型的肿瘤抑制因子，其失活驱动了侵袭性PDAC亚群中的代谢重编程，并指出了这些肿瘤的潜在治疗脆弱性。因此增强了氧化磷酸化，同时减少了糖酵解。这种代谢变化对线粒体呼吸和脂肪酸氧化的小分子抑制剂产生选择性脆弱性。总的来说，这些发现揭示了ISL2作为一种新型的肿瘤抑制因子，其失活驱动了侵袭性PDAC亚群中的代谢重编程，并指出了这些肿瘤的潜在治疗脆弱性。