小柯机器人

美国约翰·霍普金斯大学医学院Andrew J. Holland和英国牛津大学J. Ross Chapman团队合作取得一项新成果。经过不懈努力，他们发现在17q23扩增的乳腺癌中靶向TRIM37导致中心体功能紊乱。2020年9月9日，《自然》杂志在线发表了这项成果。

研究人员发现在17q23扩增的癌细胞中，中心体耗竭导致合成致死，17q23扩增是一种复发拷贝数畸变，其存在与约9%的原发性乳腺癌肿瘤中，并与高度基因组不稳定性相关。具体来说，小分子抑制polo-like激酶4（PLK4）会诱导中心体耗竭，从而引起细胞有丝分裂受损，该细胞表现出扩增子诱导的TRIM37过表达。

为了解释这种现象，研究人员把TRIM37作为中心粒周围物质的负调节因子。在缺乏中心体的17q23扩增细胞中，TRIM37升高会阻止包含中心粒周围物质病灶的形成-这些病灶具有微管成核能力，微管成核能力是在没有中心体情况下成功进行细胞分裂所必需的。最后，研究发现过表达TRIM37通过延迟中心体成熟和有丝分裂染色体分离而导致基因组不稳定，从而增加了有丝分裂错误的发生频率。

总而言之，这些发现揭示了在17q23扩增乳腺癌中TRIM37依赖的基因组不稳定是促进肿瘤发生的驱动性事件，并为靶向中心体治疗这些癌症提供了依据。

据悉，基因组不稳定性是癌症的标志，并且在乳腺癌发生和发展过程中起着关键作用。聚ADP核糖聚合酶抑制剂在治疗缺乏同源重组乳腺癌中的成功应用例证了合成致死性基因相互作用在治疗由基因组不稳定性导致乳腺癌中的效用。鉴于同源重组缺陷仅存在于部分乳腺癌中，因此有必要确定基因组不稳定的其他诱导机制和在癌症治疗中利用这些缺陷的靶向策略。

附：英文原文

Title: Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer

Author: 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

Issue&Volume: 2020-09-09

Abstract: Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer1,2. 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 instability3. 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 instability4,5,6. 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

Source: https://www.nature.com/articles/s41586-020-2690-1

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