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人类染色体主要由携带基因的脱氧核糖核酸（DNA）双链螺旋构成，基因不稳定可造成细胞有丝分裂失控而疯狂生长，这是癌细胞的重要标志之一，并且对乳腺癌的发生和发展具有关键作用。同源重组是修复DNA的主要机制，多腺苷二磷酸核糖聚合酶（PARP）抑制剂可有效治疗DNA同源重组修复功能缺陷的乳腺癌。不过，DNA同源重组修复功能缺陷仅存在于一部分乳腺癌，故有必要明确基因不稳定所致乳腺癌的其他机制及其靶向治疗策略。 2020年9月9日，全球自然科学三大旗舰期刊之一、英国《自然》正刊发表英国牛津大学、伦敦大学癌症研究院、伦敦大学国王学院、美国霍普金斯大学的研究报告，探讨了基因不稳定所致乳腺癌的关键机制及其靶向治疗策略。该研究与美国路德维希癌症研究所、圣迭戈加利福尼亚大学（加利福尼亚大学圣地亚哥分校）当天同时发表的研究不谋而合，可谓英雄所见略同。 细胞有丝分裂期间形成的纺锤体由细胞微管构成，而细胞微管由细胞中心体负责催化。细胞中心体在每个细胞有丝分裂周期复制一次，其过程受到丝氨酸苏氨酸蛋白质激酶极样激酶4（PLK4）控制。当PLK4受到化学抑制时，细胞分裂将继续进行，而不需细胞中心体复制，从而产生无细胞中心体的细胞，这些细胞表现为细胞中心体纺锤体组装延迟。 泛素连接酶TRIM37低表达可加速不需中心体的纺锤体组装，并促进PLK4抑制后的细胞增殖，而TRIM37高表达可抑制不需中心体的纺锤体组装，从而导致有丝分裂失败和细胞增殖停止。 TRIM37基因所在的17号染色体长臂第2区第3条带（17q23）扩增可见于大约10%的乳腺癌，此类乳腺癌对PLK4抑制剂高度敏感。灭活TRIM37可促进不需细胞中心体的细胞有丝分裂，因为TRIM37可阻止PLK4形成凝聚体，催化组装不需要细胞中心体的纺锤体。相反，TRIM37高表达通过降解分子量为192千道尔顿的细胞中心体蛋白质（CEP192）可抑制细胞中心体组装纺锤体，故TRIM37是细胞有丝分裂对PLK4抑制剂敏感性的重要决定因素。 调节细胞有丝分裂的细胞中心体如果被耗尽，可诱发17q23扩增癌细胞死亡，17q23扩增是基因拷贝数畸变的常见原因，并与基因不稳定程度密切相关。利用PLK4小分子抑制剂可引起细胞中心体耗尽，从而触发TRIM37过表达细胞有丝分裂期死亡。TRIM37可抑制细胞中心体的中心粒周物质，对于缺乏细胞中心体的17q23扩增细胞，TRIM37过表达可阻止中心粒周物质聚集，从而阻止细胞微管构成纺锤体，最终阻止细胞有丝分裂。此外，TRIM37过表达可延迟细胞中心体成熟并分离进入细胞有丝分裂，从而增加有丝分裂错误率，引起基因不稳定。 因此，两项研究结果表明，PLK4抑制后的细胞组装纺锤体取决于细胞中心体TRIM37水平，TRIM37引起基因不稳定是17q23扩增乳腺癌的关键机制，为此类乳腺癌的细胞中心体靶向治疗奠定了基础。 Nature. 2020 Sep 9. Online ahead of print. Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer. Zhong Y. Yeow, Bramwell G. Lambrus, Rebecca Marlow, Kevin H. Zhan, Mary-Anne Durin, Lauren T. Evans, Phillip M. Scott, Thao Phan, Elizabeth Park, Lorena A. Ruiz, Daniela Moralli, Eleanor G. Knight, Luned M. Badder, Daniela Novo, Syed Haider, Catherine M. Green, Andrew N. J. Tutt, Christopher J. Lord, J. Ross Chapman, Andrew J. Holland. University of Oxford, Oxford, UK; Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Institute of Cancer Research, London, UK; King's College London, London, UK. Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer. The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability. Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material—these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers. DOI: 10.1038/s41586-020-2690-1 Nature. 2020 Sep 9. Online ahead of print. TRIM37 controls cancer-specific vulnerability to PLK4 inhibition. Franz Meitinger, Midori Ohta, Kian-Yong Lee, Sadanori Watanabe, Robert L. Davis, John V. Anzola, Ruth Kabeche, David A. Jenkins, Andrew K. Shiau, Arshad Desai, Karen Oegema. Ludwig Institute for Cancer Research, La Jolla, CA, USA; University of California, San Diego, La Jolla, CA, USA. Centrosomes catalyse the formation of microtubules needed to assemble the mitotic spindle apparatus. Centrosomes themselves duplicate once per cell cycle, in a process that is controlled by the serine/threonine protein kinase PLK4. When PLK4 is chemically inhibited, cell division proceeds without centrosome duplication, generating centrosome-less cells that exhibit delayed, acentrosomal spindle assembly. Whether PLK4 inhibitors can be leveraged as a treatment for cancer is not yet clear. Here we show that acentrosomal spindle assembly following PLK4 inhibition depends on levels of the centrosomal ubiquitin ligase TRIM37. Low TRIM37 levels accelerate acentrosomal spindle assembly and improve proliferation following PLK4 inhibition, whereas high TRIM37 levels inhibit acentrosomal spindle assembly, leading to mitotic failure and cessation of proliferation. The Chr17q region containing the TRIM37 gene is frequently amplified in neuroblastoma and in breast cancer, rendering these cancer types highly sensitive to PLK4 inhibition. We find that inactivating TRIM37 improves acentrosomal mitosis because TRIM37 prevents PLK4 from self-assembling into centrosome-independent condensates that serve as ectopic microtubule-organizing centres. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly through a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is an essential determinant of mitotic vulnerability to PLK4 inhibition. Linkage of TRIM37 to prevalent cancer-associated genomic changes (including 17q gain in neuroblastoma and 17q23 amplification in breast cancer) may offer an opportunity to use PLK4 inhibition to trigger selective mitotic failure and provide new avenues to treatments for these cancers. DOI: 10.1038/s41586-020-2710-1
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