Alfarano Gabriele, Audano Matteo, Di Chiaro Pierluigi, Balestrieri Chiara, Milan Marta, Polletti Sara, Spaggiari Paola, Zerbi Alessandro, Diaferia Giuseppe Riccardo, Mitro Nico, Natoli Gioacchino
Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
Gut. 2023 Jan;72(1):109-128. doi: 10.1136/gutjnl-2021-325811. Epub 2022 May 13.
Pancreatic ductal adenocarcinomas (PDACs) include heterogeneous mixtures of low-grade cells forming pseudoglandular structures and compact nests of high-grade cells organised in non-glandular patterns. We previously reported that low-grade PDAC cells display high expression of interferon regulatory factor 1 (IRF1), a pivotal transcription factor of the interferon (IFN) system, suggesting grade-specific, cell-intrinsic activation of IFN responses. Here, we set out to determine the molecular bases and the functional impact of the activation of IFN-regulated responses in human PDACs.
We first confirmed the correlation between glandular differentiation and molecular subtypes of PDAC on the one hand, and the expression of IRF1 and IFN-stimulated genes on the other. We next used unbiased omics approaches to systematically analyse basal and IFN-regulated responses in low-grade and high-grade PDAC cells, as well as the impact of IRF1 on gene expression programmes and metabolic profiles of PDAC cells.
High-level expression of IRF1 in low-grade PDAC cells was controlled by endodermal lineage-determining transcription factors. IRF1-regulated gene expression equipped low-grade PDAC cells with distinctive properties related to antigen presentation and processing as well as responsiveness to IFN stimulation. Notably, IRF1 also controlled the characteristic metabolic profile of low-grade PDAC cells, suppressing both mitochondrial respiration and fatty acid synthesis, which may in part explain its growth-inhibiting activity.
IRF1 links endodermal differentiation to the expression of genes controlling antigen presentation and processing as well as to the specification of the metabolic profile characteristic of classical PDAC cells.
胰腺导管腺癌（PDAC）包含形成假腺管结构的低级别细胞和以非腺管模式组织的高级别细胞紧密巢团的异质混合物。我们之前报道过低级别PDAC细胞显示出干扰素调节因子1（IRF1）的高表达，IRF1是干扰素（IFN）系统的关键转录因子，提示IFN反应存在级别特异性、细胞内在性激活。在此，我们着手确定人类PDAC中IFN调节反应激活的分子基础及其功能影响。
我们首先证实了一方面PDAC的腺管分化与分子亚型之间的相关性，另一方面IRF1和IFN刺激基因的表达之间的相关性。接下来，我们使用无偏组学方法系统分析低级别和高级别PDAC细胞中的基础和IFN调节反应，以及IRF1对PDAC细胞基因表达程序和代谢谱的影响。
低级别PDAC细胞中IRF1的高水平表达受内胚层谱系决定转录因子控制。IRF1调节的基因表达赋予低级别PDAC细胞与抗原呈递和加工以及对IFN刺激反应性相关的独特特性。值得注意的是，IRF1还控制低级别PDAC细胞的特征性代谢谱，抑制线粒体呼吸和脂肪酸合成，这可能部分解释了其生长抑制活性。
IRF1将内胚层分化与控制抗原呈递和加工的基因表达以及经典PDAC细胞特征性代谢谱的特征联系起来。
