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Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma.
Cancer Discovery ( IF 28.2 ) Pub Date : 2020-06-01 , DOI: 10.1158/2159-8290.cd-19-0620
Nathiya Muthalagu 1 , Tiziana Monteverde 2 , Ximena Raffo-Iraolagoitia 1 , Robert Wiesheu 2 , Declan Whyte 2 , Ann Hedley 1 , Sarah Laing 2 , Björn Kruspig 2 , Rosanna Upstill-Goddard 3 , Robin Shaw 1 , Sarah Neidler 2 , Curtis Rink 1 , Saadia A Karim 1 , Katarina Gyuraszova 2 , Colin Nixon 1 , William Clark 1 , Andrew V Biankin 3 , Leo M Carlin 1, 2 , Seth B Coffelt 1, 2 , Owen J Sansom 1, 2 , Jennifer P Morton 1, 2 , Daniel J Murphy 1, 2
Affiliation  

MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumors, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression of the type I interferon (IFN) pathway by the combined actions of MYC and KRAS, and we present evidence of repressive MYC–MIZ1 complexes binding directly to the promoters of the genes encodiing the type I IFN regulators IRF5, IRF7, STAT1, and STAT2. Derepression of IFN regulator genes allows pancreatic tumor infiltration by B and natural killer (NK) cells, resulting in increased survival. Significance: We define herein a novel mechanism of evasion of NK cell–mediated immunity through the combined actions of endogenously expressed mutant KRAS and modestly deregulated expression of MYC, via suppression of the type I IFN pathway. Restoration of IFN signaling may improve outcomes for patients with PDAC. This article is highlighted in the In This Issue feature, [p. 747][1] [1]: /lookup/volpage/10/747?iss=6

中文翻译:

I 型干扰素通路的抑制是胰腺导管腺癌中 NK 和 B 细胞的 MYC 和 KRAS 依赖性逃避的基础。

MYC 与胰腺癌的发展和进展有关,但导致肿瘤发展所需的 MYC 失调的精确水平一直难以确定。我们使用从 Rosa26 基因座驱动的适度升高的人类 MYC 表达来研究小鼠中由近似 MYC 三体性引起的胰腺表型。我们表明,仅这一水平的 MYC 就足以驱动胰腺神经内分泌肿瘤,并加速 KRAS 引发的前体病变进展为转移性胰腺导管腺癌 (PDAC)。我们的表型通过 MYC 和 KRAS 的联合作用暴露了 I 型干扰素 (IFN) 途径的抑制,并且我们提供了抑制性 MYC-MIZ1 复合物直接与编码 I 型干扰素调节因子 IRF5、IRF7、 STAT1 和 STAT2。干扰素调节基因的去抑制允许 B 细胞和自然杀伤 (NK) 细胞浸润胰腺肿瘤,从而提高存活率。意义:我们在本文中定义了一种逃避 NK 细胞介导免疫的新机制,通过抑制 I 型 IFN 途径,通过内源性表达的突变 KRAS 和 MYC 的适度失调表达的联合作用。恢复 IFN 信号可能会改善 PDAC 患者的预后。本文在 In This Issue 功能中突出显示,[p. 747][1][1]:/lookup/volpage/10/747?iss=6 我们在此定义了一种逃避 NK 细胞介导免疫的新机制,通过抑制 I 型 IFN 途径,通过内源性表达的突变 KRAS 和适度失调的 MYC 表达的联合作用。恢复 IFN 信号可能会改善 PDAC 患者的预后。本文在 In This Issue 功能中突出显示,[p. 747][1][1]:/lookup/volpage/10/747?iss=6 我们在此定义了一种逃避 NK 细胞介导免疫的新机制,通过抑制 I 型 IFN 途径,通过内源性表达的突变 KRAS 和适度失调的 MYC 表达的联合作用。恢复 IFN 信号可能会改善 PDAC 患者的预后。本文在 In This Issue 功能中突出显示,[p. 747][1][1]:/lookup/volpage/10/747?iss=6
更新日期:2020-06-01
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