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Senescence-associated reprogramming promotes cancer stemness

机译:衰老相关的重编程促进癌症干

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摘要

Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-) malignant cells(1,2). Key signalling components of the senescence machinery, such as p16(INK4a), p21(CIP1) and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness')(3). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from E mu-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.
机译:细胞衰老是一种应激反应的细胞周期阻滞程序,它终止了恶性前细胞的进一步扩增(1,2)。衰老机制的关键信号成分,例如p16(INK4a),p21(CIP1)和p53,以及组蛋白H3(H3K9me3)上赖氨酸9的三甲基化,也起着干细胞功能的关键调节器的作用。称为“干”(3)。在癌细胞中,干性的获得可能对肿瘤的侵袭性和临床结果产生深远的影响。在这里,我们调查了化学疗法诱导的衰老是否可以改变恶性细胞与干细胞相关的特性。基因表达和功能分析比较了来自E mu-Myc转基因小鼠的衰老和非衰老B细胞淋巴瘤,显示成年组织干细胞标志,活化的Wnt信号传导和衰老中不同的干细胞标志物显着上调。使用针对H3K9me3或p53的衰老的遗传可转换模型来模拟从停滞状态的自发逃逸,我们发现与实际上几乎相同的种群相比,衰老释放的细胞重新进入了具有强烈增强的Wnt依赖性克隆生长潜能的细胞周期。同样接受化学疗法但从未衰老。在体内,这些先前衰老的细胞具有更高的肿瘤起始潜力。值得注意的是,在急性淋巴细胞性白血病和急性髓细胞性白血病的可调节p53的模型中,衰老的暂时执行将非干性白血病细胞重编程为可自我更新的,引发白血病的干细胞。我们的数据得到了人类癌细胞系和人类血液恶性肿瘤的主要样本的一致结果的进一步支持,这些数据表明,与衰老相关的茎干是一种出乎意料的,具有细胞自主性的特征,一旦脱离细胞就会发挥其有害的,高度侵袭性的生长潜力周期阻滞,并丰富了复发肿瘤。这些发现对癌症治疗具有深远的意义,并为癌细胞的可塑性提供了新的机理见解。

著录项

  • 来源
    《Nature》 |2018年第7686期|96-100|共5页
  • 作者单位

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, D-69120 Heidelberg, Germany|Deutsch Krebsforschungszentrum DKFZ, German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, Partner Site Berlin, Berlin, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany;

    Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10065 USA;

    Helmholtz Assoc, Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany;

    Charite, Dept Pathol, Berlin, Germany;

    Charite, Dept Pathol, Berlin, Germany;

    Vienna Bioctr, IMP, Dr Bohr Gasse 7, A-1030 Vienna, Austria;

    Univ Strasbourg, Equipe Labellisee Ligue Canc, Dept Funct Genom & Canc,INSERM,U964, Inst Genet & Biol Mol & Cellulaire,CNRS,UMR7104, F-67400 Illkirch Graffenstaden, France;

    Helmholtz Assoc, Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany;

    German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, D-69120 Heidelberg, Germany|Deutsch Krebsforschungszentrum DKFZ, German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, Partner Site Berlin, Berlin, Germany|Heidelberg Inst Stem Cell Technol & Expt Med HI S, Neuenheimer Feld 280, D-69120 Heidelberg, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, D-69120 Heidelberg, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, Partner Site Berlin, Berlin, Germany|Helmholtz Assoc, Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany|Berlin Inst Hlth, Anna Louisa Karsch Str 2, D-10178 Berlin, Germany;

    Vienna Bioctr, IMP, Dr Bohr Gasse 7, A-1030 Vienna, Austria;

    Univ Strasbourg, Equipe Labellisee Ligue Canc, Dept Funct Genom & Canc,INSERM,U964, Inst Genet & Biol Mol & Cellulaire,CNRS,UMR7104, F-67400 Illkirch Graffenstaden, France;

    German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, D-69120 Heidelberg, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, Partner Site Berlin, Berlin, Germany|Berlin Inst Hlth, Anna Louisa Karsch Str 2, D-10178 Berlin, Germany;

    Helmholtz Assoc, Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany|Luxembourg Inst Hlth, 1A-B Rue Thomas Edison, L-1455 Strassen, Luxembourg;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, D-69120 Heidelberg, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, Partner Site Berlin, Berlin, Germany|Helmholtz Assoc, Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany;

    Charite, Med Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany|Charite, Mol Krebsforschungszentrum MKFZ, Virchow Campus, D-13353 Berlin, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, D-69120 Heidelberg, Germany|German Canc Consortium, Deutsch Konsortium Translat Krebsforsch, Partner Site Berlin, Berlin, Germany|Helmholtz Assoc, Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany|Berlin Inst Hlth, Anna Louisa Karsch Str 2, D-10178 Berlin, Germany;

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  • 入库时间 2022-08-18 02:51:26

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