Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival. The exogenous ISL2 expression or CRISPR-mediated upregulation of the endogenous loci reduces cell proliferation. Mechanistically, ISL2 regulates the expression of metabolic genes, and its depletion increases oxidative phosphorylation (OXPHOS). As such, ISL2-depleted human PDA cells are sensitive to the inhibitors of mitochondrial complex I in vitro and in vivo. Spatial transcriptomic analysis shows heterogeneous intratumoral ISL2 expression, which correlates with the expression of critical metabolic genes. These findings nominate ISL2 as a putative tumor suppressor whose inactivation leads to increased mitochondrial metabolism that may be exploitable therapeutically.

胰腺导管腺癌 (PDA) 细胞重新编程其转录和代谢程序，以在营养不良的肿瘤微环境中生存。通过体内通过 CRISPR 筛选，我们发现 islet-2 (ISL2) 作为候选肿瘤抑制因子可调节侵袭性 PDA 生长。值得注意的是，ISL2 是一种核和染色质相关转录因子，在 PDA 肿瘤中表观遗传沉默，高启动子 DNA 甲基化或其表达减少与患者存活率低相关。外源性 ISL2 表达或 CRISPR 介导的内源性位点上调会减少细胞增殖。从机制上讲，ISL2 调节代谢基因的表达，其消耗会增加氧化磷酸化 (OXPHOS)。因此，ISL2 耗尽的人 PDA 细胞在体外和体内对线粒体复合物 I 的抑制剂敏感. 空间转录组学分析显示异质性肿瘤内 ISL2 表达，这与关键代谢基因的表达相关。这些发现将 ISL2 指定为推定的肿瘤抑制因子，其失活会导致线粒体代谢增加，这可能在治疗上是可利用的。