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破碎的染色体如何使癌细胞具有耐药性

   2020-12-24 medicalxpress220
核心提示:在2020年12月23日在线《自然》杂志上发表的一篇论文中,加州大学圣地亚哥分校医学院和路德维希癌症研究所加州大学圣地亚哥分校的研究人员与纽约和英国的同事一起描述了被称为“染色体脱色”的现象如何分解染色体,然后以最终促进癌细胞生长的方式重新组装。

癌症是世界上最大的健康危机之一,因为与某些疾病不同,癌症是一个不断发展的目标,不断逃避和抵制治疗。

在2020年12月23日在线《自然》杂志上发表的一篇论文中,加州大学圣地亚哥分校医学院和路德维希癌症研究所加州大学圣地亚哥分校的研究人员与纽约和英国的同事一起描述了被称为“染色体脱色”的现象如何分解染色体,然后以最终促进癌细胞生长的方式重新组装。

嗜铬菌病是细胞历史上的灾难性突变事件,涉及其基因组的大规模重排,而不是随着时间的推移逐渐获得重排和突变。基因组重排是许多癌症的关键特征,它可使突变的细胞生长或生长更快,而不受抗癌疗法的影响。

该论文的共同资深作者,医学,神经科学和细胞学教授唐·克利夫兰(Don Cleveland)博士的实验室博士后研究员,第一作者Ofer Shoshani博士说:“这些重排可以一步完成。”和圣地亚哥圣地亚哥医学院的分子医学。

“在发生染色体脱色病的过程中,细胞中的一条染色体被破碎成许多碎片,在某些情况下成百上千,然后以重新排列的顺序重新组装。一些碎片丢失了,而另一些则作为染色体外DNA(ecDNA)持续存在。其中某些ecDNA元素可以促进癌细胞生长并形成称为“双重分钟”的微小染色体。”

去年,路德维希癌症研究所加州大学圣地亚哥分校的科学家发表的研究发现,在许多类型的癌症中,多达一半的癌细胞都含有携带促癌基因的ecDNA。

在最新研究中,Cleveland,Shosani和同事利用染色体结构的直接可视化来确定基因扩增的步骤以及对甲氨蝶呤耐药的机制,甲氨蝶呤是最早的化疗药物之一,至今仍被广泛使用。

该团队与英国韦尔康格桑格研究所癌症,衰老和体细胞突变负责人彼得·坎贝尔(Peter J.Campbell)共同资深研究员合作,对产生耐药性的细胞的整个基因组进行了测序,揭示了染色体破碎迅速启动赋予抗癌治疗抗性的ecDNA携带基因的形成。

科学家还确定了染色体内基因扩增后,染色质去磷酸酶如何驱动ecDNA的形成。

Shoshani说:“染色体除虫病将染色体内扩增(内部)转化为染色体外(外部)扩增,然后扩增后的ecDNA可以重新整合到染色体位置,以响应化学疗法或放射疗法对DNA的损害。” “新的工作突出chromothripsis的作用在扩增DNA的癌细胞生命周期的所有重要阶段,解释如何癌症细胞可以变得更具侵略性或耐药。”

克利夫兰说:“我们鉴定出重复的DNA破碎是抗癌药耐药性的驱动力,以及重组破碎的染色体片段所必需的DNA修复途径的发现,已经使合理设计组合药物疗法可以防止癌症患者产生耐药性,从而改善结果。”

这些发现解决了所谓的九项癌症治疗发展大挑战中的一项,这是美国国家癌症研究所与英国癌症研究英国公司(全球最大的独立癌症研究和认识慈善机构)的联合伙伴关系。


How shattered chromosomes make cancer cells drug-resistant

Cancer is one of the world's greatest health afflictions because, unlike some diseases, it is a moving target, constantly evolving to evade and resist treatment.

In a paper published in the December 23, 2020 online issue of Nature, researchers at University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research, with colleagues in New York and the United Kingdom, describe how a phenomenon known as "chromothripsis" breaks up chromosomes, which then reassemble in ways that ultimately promote cancer cell growth.

Chromothripsis is a catastrophic mutational event in a cell's history that involves massive rearrangement of its genome, as opposed to a gradual acquisition of rearrangements and mutations over time. Genomic rearrangement is a key characteristic of many cancers, allowing mutated cells to grow or grow faster, unaffected by anti-cancer therapies.

"These rearrangements can occur in a single step," said first author Ofer Shoshani, Ph.D., a postdoctoral fellow in the lab of the paper's co-senior author Don Cleveland, Ph.D., professor of medicine, neurosciences and cellular and molecular medicine at UC San Diego School of Medicine.

"During chromothripsis, a chromosome in a cell is shattered into many pieces, hundreds in some cases, followed by reassembly in a shuffled order. Some pieces get lost while others persist as extra-chromosomal DNA (ecDNA). Some of these ecDNA elements promote cancer cell growth and form minute-sized chromosomes called 'double minutes.'"

Research published last year by scientists at the UC San Diego branch of the Ludwig Institute for Cancer Research found that up to half of all cancer cells in many types of cancers contain ecDNA carrying cancer-promoting genes.

In the latest study, Cleveland, Shoshani and colleagues employed direct visualization of chromosome structure to identify the steps in gene amplification and the mechanism underlying resistance to methotrexate, one of the earliest chemotherapy drugs and still widely used.

In collaboration with co-senior author Peter J. Campbell, Ph.D., head of cancer, aging and somatic mutation at Wellcome Sanger Institute in the United Kingdom, the team sequenced the entire genomes of cells developing drug resistance, revealing that chromosome shattering jump-starts formation of ecDNA-carrying genes that confer anti-cancer therapy resistance.

The scientists also identified how chromothripsis drives ecDNA formation after gene amplification inside a chromosome.

"Chromothripsis converts intra-chromosomal amplifications (internal) into extra-chromosomal (external) amplifications and that amplified ecDNA can then reintegrate into chromosomal locations in response to DNA damage from chemotherapy or radiotherapy," said Shoshani. "The new work highlights the role of chromothripsis at all critical stages in the life cycle of amplified DNA in cancer cells, explaining how cancer cells can become more aggressive or drug-resistant."

Said Cleveland: "Our identifications of repetitive DNA shattering as a driver of anti-cancer drug resistance and of DNA repair pathways necessary for reassembling the shattered chromosomal pieces has enabled rational design of combination drug therapies to prevent development of drug resistance in cancer patients, thereby improving their outcome."

The findings address one of the so-called nine Grand Challenges for cancer therapy development, a joint partnership between the National Cancer Institute in the United States and Cancer Research UK, the world's largest independent cancer research and awareness charity.


 
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