Institute of Medical Microbiology and Hygiene, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute of Medical Bioinformatics and Systems Medicine, Medical Center -, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Cell Death Dis. 2022 Apr 7;13(4):315. doi: 10.1038/s41419-022-04768-y.
Micronuclei are DNA-containing structures separate from the nucleus found in cancer cells. Micronuclei are recognized by the immune sensor axis cGAS/STING, driving cancer metastasis. The mitochondrial apoptosis apparatus can be experimentally triggered to a non-apoptotic level, and this can drive the appearance of micronuclei through the Caspase-activated DNAse (CAD). We tested whether spontaneously appearing micronuclei in cancer cells are linked to sub-lethal apoptotic signals. Inhibition of mitochondrial apoptosis or of CAD reduced the number of micronuclei in tumor cell lines as well as the number of chromosomal misalignments in tumor cells and intestinal organoids. Blockade of mitochondrial apoptosis or deletion of CAD reduced, while experimental activation CAD, STING-dependently, enhanced aggressive growth of tumor cells in vitro. Deletion of CAD from human cancer cells reduced metastasis in xenograft models. CAD-deficient cells displayed a substantially altered gene-expression profile, and a CAD-associated gene expression 'signature' strongly predicted survival in cancer patients. Thus, low-level activity in the mitochondrial apoptosis apparatus operates through CAD-dependent gene-induction and STING-activation and has substantial impact on metastasis in cancer.
微核是指在癌细胞中发现的、与细胞核分离的含 DNA 结构。微核被免疫传感器轴 cGAS/STING 识别，从而驱动癌症转移。实验上可以触发线粒体凋亡装置到非凋亡水平，这可以通过 Caspase-activated DNAse (CAD) 驱动微核的出现。我们测试了癌细胞中自发出现的微核是否与亚致死性凋亡信号有关。抑制线粒体凋亡或 CAD 减少了肿瘤细胞系中的微核数量，以及肿瘤细胞和肠类器官中的染色体错位数量。线粒体凋亡的阻断或 CAD 的缺失减少了，而实验性地激活 CAD，STING 依赖性地，增强了肿瘤细胞在体外的侵袭性生长。从人源癌细胞中缺失 CAD 减少了异种移植模型中的转移。CAD 缺失的细胞表现出明显改变的基因表达谱，而与 CAD 相关的基因表达“特征”强烈预测癌症患者的生存。因此，线粒体凋亡装置的低水平活性通过 CAD 依赖性基因诱导和 STING 激活起作用，并对癌症转移有重大影响。
