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Necroptosis microenvironment directs lineage commitment in liver cancer

机译：坏死病微环境指导肝癌的血统承诺

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摘要

Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.
机译：原发性肝癌是一个主要的健康问题。它包括肝细胞癌（HCC）和肝内胆管癌（ICC），它们在形态，转移潜能和对治疗的反应方面存在明显差异。然而，将转化的肝细胞投向HCC或ICC的调节分子和组织环境在很大程度上是未知的。在这里，我们显示肝脏微环境表观遗传学在肝肿瘤发生的镶嵌小鼠模型中沿袭定型。坏死病相关的肝细胞因子微环境决定了ICC从致癌转化的肝细胞中生长出来，而如果包含相同致癌驱动因子的肝细胞被凋亡性肝细胞包围，则它们会产生HCC。小鼠HCC和ICC的表观基因组和转录组分析表明Tbx3和Prdm5是主要的微环境依赖性和表观遗传调控的谱系承诺因子，在人类中是保守的。在一起，我们的结果提供了对肝肿瘤发生中谱系承诺的见解，并从分子上解释了为什么常见的破坏肝脏的危险因素会导致HCC或ICC。

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  • 来源
    《Nature》 |2018年第7725期|69-75|共7页
  • 作者

    Seehawer Marco; Heinzmann Florian; DArtista Luana; Harbig Jule; Roux Pierre-Francois; Hoenicke Lisa; Dang Hien; Klotz Sabrina; Robinson Lucas; Dore Gregory; Rozenblum Nir; Kang Tae-Won; Chawla Rishabh; Buch Thorsten; Vucur Mihael; Roth Mareike; Zuber Johannes; Luedde Tom; Sipos Bence; Longerich Thomas; Heikenwaelder Mathias; Wang Xin Wei; Bischof Oliver; Zender Lars;

  • 作者单位

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

    Inst Pasteur, Nucl Org & Oncogenesis Unit, Dept Cell Biol & Infect, Paris, France;

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

    NCI, Lab Human Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA;

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

    Inst Pasteur, Nucl Org & Oncogenesis Unit, Dept Cell Biol & Infect, Paris, France;

    Inst Pasteur, Nucl Org & Oncogenesis Unit, Dept Cell Biol & Infect, Paris, France;

    Inst Pasteur, Nucl Org & Oncogenesis Unit, Dept Cell Biol & Infect, Paris, France;

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

    Univ Zurich, Inst Lab Anim Sci, Schlieren, Switzerland;

    RWTH Univ Hosp Aachen, Dept Gastroenterol Digest Dis & Intens Care Med, Dept Med 3, Aachen, Germany;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Vienna, Austria;

    RWTH Univ Hosp Aachen, Dept Gastroenterol Digest Dis & Intens Care Med, Dept Med 3, Aachen, Germany;

    Univ Tubingen, Inst Pathol, Tubingen, Germany;

    Univ Hosp Heidelberg, Inst Pathol, Heidelberg, Germany;

    German Canc Res Ctr, Div Chron Inflammat & Canc, Heidelberg, Germany;

    NCI, Lab Human Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA;

    Inst Pasteur, Nucl Org & Oncogenesis Unit, Dept Cell Biol & Infect, Paris, France;

    Univ Hosp Tuebingen, Dept Internal Med 8, Tubingen, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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