The portrait of liver cancer is shaped by mitochondrial genetics.
The portrait of liver cancer is shaped by mitochondrial genetics.
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肝癌的画像是由线粒体遗传学塑造的。
DOI：
10.1016/j.celrep.2021.110254
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发表时间：
2022-01-18
期刊：
影响因子：
8.8
通讯作者：
Germain D
中科院分区：
文献类型：
--
作者：
Chattopadhyay M;Jenkins EC;Lechuga-Vieco AV;Nie K;Fiel MI;Rialdi A;Guccione E;Enriquez JA;Sia D;Lujambio A;Germain D
癌症的异质性和演变尚未完全了解。在这里，我们表明，正常肝脏的线粒体DNA形状肿瘤的进展，组织学和免疫环境之前，获得致癌突变。使用共变性小鼠，我们表明，线粒体DNA决定了正常肝脏中线粒体未折叠蛋白反应（UPRmt）的表达。UPRmt阳性肝脏中致癌突变的激活增加了肿瘤发生率和组织学异质性。此外，在UPRmt阳性小鼠的子集中，发生侵袭性肝癌。正常肝脏的RNA测序（RNA-seq）分析揭示，在该亚组中，PAPP-A/DDR2/SNAIL侵袭轴沿着升高的胶原蛋白预先存在。由于PAPP-A促进免疫逃避，我们分析了免疫特征，发现它们的肝脏受到免疫抑制。此外，PAPP-A特征识别人类肝细胞癌（HCC）的免疫耗竭亚群。我们的数据表明，正常肝脏的mtDNA在获得致癌突变后形成整个肝癌画像。Chattopadhyay等人使用仅线粒体DNA不同的小鼠，表明正常肝脏的线粒体遗传学在获得致癌突变之前塑造了肿瘤进展、组织学和免疫环境。他们描述了一种基因特征，这种特征是小鼠和人类中最具侵袭性的肝癌。
Cancer heterogeneity and evolution are not fully understood. Here, we show that mitochondrial DNA of the normal liver shapes tumor progression, histology, and immune environment prior to the acquisition of oncogenic mutation. Using conplastic mice, we show that mtDNA dictates the expression of the mitochondrial unfolded protein response (UPRmt) in the normal liver. Activation of oncogenic mutations in UPRmt-positive liver increases tumor incidence and histological heterogeneity. Further, in a subset of UPRmt-positive mice, invasive liver cancers develop. RNA sequencing (RNA-seq) analysis of the normal liver reveals that, in this subset, the PAPP-A/DDR2/SNAIL axis of invasion pre-exists along with elevated collagen. Since PAPP-A promotes immune evasion, we analyzed the immune signature and found that their livers are immunosuppressed. Further, the PAPP-A signature identifies the immune exhausted subset of hepatocellular carcinoma (HCC) in humans. Our data suggest that mtDNA of normal liver shapes the entire liver cancer portrait upon acquisition of oncogenic mutations. Using mice that differ only in mitochondrial DNA, Chattopadhyay et al. show that mitochondrial genetics of the normal liver shapes tumor progression, histology, and immune environment prior to the acquisition of oncogenic mutation. They describe a genetic signature that characterizes the most aggressive liver cancers in both mice and humans.
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