Northwestern University Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Chicago, IL 60611, USA.
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
Dev Cell. 2022 Jun 6;57(11):1331-1346.e9. doi: 10.1016/j.devcel.2022.04.014. Epub 2022 May 3.
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，以在营养贫乏的肿瘤微环境中存活。通过体内 CRISPR 筛选，我们发现胰岛 2 （ISL2）是一种候选肿瘤抑制因子，可调节侵袭性 PDA 的生长。值得注意的是，ISL2 是一种核和染色质相关的转录因子，在 PDA 肿瘤中被表观遗传沉默，高启动子 DNA 甲基化或其表达降低与患者预后不良相关。外源性 ISL2 表达或 CRISPR 介导的内源性基因座上调可降低细胞增殖。在机制上，ISL2 调节代谢基因的表达，其缺失会增加氧化磷酸化（OXPHOS）。因此，ISL2 耗尽的人 PDA 细胞对体外和体内线粒体复合物 I 的抑制剂敏感。空间转录组学分析显示肿瘤内异质性的 ISL2 表达，与关键代谢基因的表达相关。这些发现将 ISL2 作为一种潜在的肿瘤抑制因子，其失活会导致线粒体代谢增加，这可能具有治疗潜力。
