Santaguida Stefano, Richardson Amelia, Iyer Divya Ramalingam, M'Saad Ons, Zasadil Lauren, Knouse Kristin A, Wong Yao Liang, Rhind Nicholas, Desai Arshad, Amon Angelika
Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 76-543, Cambridge, MA 02138, USA.
Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Dev Cell. 2017 Jun 19;41(6):638-651.e5. doi: 10.1016/j.devcel.2017.05.022.
Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways that limit the prevalence of such cells exist? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell-cycle arrest. We further show that cells with complex karyotypes exhibit features of senescence and produce pro-inflammatory signals that promote their clearance by the immune system. We propose that cells with abnormal karyotypes generate a signal for their own elimination that may serve as a means for cancer cell immunosurveillance.
非整倍体是一种核型失衡状态，是癌症的一个标志。有人提出，染色体拷贝数的变化通过调节癌症驱动基因的剂量和促进癌症基因组进化来推动疾病发展。鉴于核型异常的细胞具有癌变的可能性，那么是否存在限制此类细胞流行的途径呢？通过研究非整倍体对细胞生理学的直接影响，我们确定了消除非整倍体细胞的机制。我们发现染色体错分离会导致进一步的基因组不稳定，最终导致细胞周期停滞。我们进一步表明，具有复杂核型的细胞表现出衰老特征，并产生促炎信号，促进免疫系统对它们的清除。我们提出，核型异常的细胞会产生自我消除的信号，这可能是癌细胞免疫监视的一种方式。
