美国纪念斯隆凯特琳癌症中心Andrea Ventura团队近期取得重要工作进展，他们研究提出，工程化的染色体外癌基因扩增促进肿瘤发生。相关研究成果2024年12月18日在线发表于《自然》杂志上。

据介绍，局灶性基因扩增是最常见的癌症相关突变之一，但事实证明，在原代细胞和模式生物中进行基因工程具有挑战性。

研究人员描述了一种在细胞和小鼠中以时空控制的方式，设计由染色体外DNA（ecDNA）介导的大（超过1Mbp）局灶性扩增的一般策略。通过将ecDNA的形成与选择性标记的表达相结合，研究人员追踪了在生理条件下和特定选择压力下含ecDNA细胞的动态。

研究人员还应用这种方法来产生携带Cre诱导的Myc和Mdm2的小鼠，这些小鼠含有类似于人类癌症中发生的ecDNA。研究人员发现，工程化的ecDNA自发积累在这些动物的原代细胞中，促进其增殖、永生化和转化。最后，研究人员证明了含有Mdm2的ecDNA，在肝细胞癌的原位小鼠模型中促进肿瘤形成的能力。这些发现为了解ecDNA介导的基因扩增在肿瘤发生中的作用提供了见解。

总之，研究人员认为，这种方法对于研究ecDNA生物学的进一步未解决方面，以及开发具有特定局灶基因扩增的，人类癌症的新的临床前免疫活性小鼠模型具有重要价值。

附：英文原文

Title: Engineered extrachromosomal oncogene amplifications promote tumorigenesis

Author: Pradella, Davide, Zhang, Minsi, Gao, Rui, Yao, Melissa A., Gluchowska, Katarzyna M., Cendon-Florez, Ylenia, Mishra, Tanmay, La Rocca, Gaspare, Weigl, Moritz, Jiao, Ziqi, Nguyen, Hieu H. M., Lisi, Marta, Ozimek, Mateusz M., Mastroleo, Chiara, Chen, Kevin, Grimm, Felix, Luebeck, Jens, Zhang, Shu, Zolli, Andrea Alice, Sun, Eric G., Dameracharla, Bhargavi, Zhao, Zhengqiao, Pritykin, Yuri, Sigel, Carlie, Chang, Howard Y., Mischel, Paul S., Bafna, Vineet, Antonescu, Cristina R., Ventura, Andrea

Issue&Volume: 2024-12-18

Abstract: Focal gene amplifications are among the most common cancer-associated mutations1 but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs)2 in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harbouring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumour formation in an autochthonous mouse model of hepatocellular carcinoma. These findings offer insights into the role of ecDNA-mediated gene amplifications in tumorigenesis. We anticipate that this approach will be valuable for investigating further unresolved aspects of ecDNA biology and for developing new preclinical immunocompetent mouse models of human cancers harbouring specific focal gene amplifications.

DOI: 10.1038/s41586-024-08318-8

Source: https://www.nature.com/articles/s41586-024-08318-8