Charité - Universitätsmedizin Berlin, Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum - MKFZ, Virchow Campus, 13353 Berlin, Germany.
Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), 69120 Heidelberg, Germany.
Nature. 2018 Jan 4;553(7686):96-100. doi: 10.1038/nature25167. Epub 2017 Dec 20.
Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16, p21 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'). 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 Eμ-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.
细胞衰老（cellular senescence）是一种应激反应性细胞周期停滞程序，可终止（前）恶性细胞的进一步扩张。衰老机制的关键信号成分，如 p16、p21 和 p53，以及组蛋白 H3 赖氨酸 9 三甲基化（H3K9me3），也作为干细胞功能的关键调节剂（统称为“干性”）。在癌细胞中，干性的获得可能对肿瘤侵袭性和临床结果产生深远影响。在这里，我们研究了化疗诱导的衰老是否会改变恶性细胞与干细胞相关的特性。比较 Eμ-Myc 转基因小鼠的衰老和非衰老 B 细胞淋巴瘤的基因表达和功能分析显示，衰老的 B 细胞淋巴瘤中大量上调了成人组织干细胞特征、激活的 Wnt 信号和不同的干细胞标志物。使用靶向 H3K9me3 或 p53 的基因可切换的衰老模型来模拟自发逃避停滞状态，我们发现，与经历过相同化疗但从未衰老的几乎相同的细胞相比，从衰老中释放的细胞重新进入细胞周期时，具有更强的、Wnt 依赖性的集落形成生长潜力。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 p53 可调节的急性淋巴细胞白血病和急性髓细胞白血病模型中暂时实施衰老，被发现可将非干性白血病细胞重编程为自我更新的白血病起始干细胞。我们的数据得到了人类癌细胞系和人类血液恶性肿瘤的原发性样本中的一致结果的进一步支持，揭示了衰老相关干性是一种意外的、细胞自主的特征，它在逃避细胞周期阻滞后发挥其有害的、高度侵袭性的生长潜力，并在复发肿瘤中富集。这些发现对癌症治疗具有深远的意义，并为癌症细胞的可塑性提供了新的机制见解。
