Investigating the roles of oncogenic extrachromosomal circular DNAs in cancer

研究致癌染色体外环状 DNA 在癌症中的作用

基本信息

  • 批准号:
    10718423
  • 负责人:
  • 金额:
    $ 56.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-01 至 2028-07-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Increased oncogene expression mediated by focal amplifications is a common mechanism for oncogene activation in human cancers. Two major mechanisms leading to oncogene amplification have been described: chromosomal amplification and non-chromosomal amplification. The latter mechanism is characterized by the presence of multiple copies of circular DNAs that are thought to originate following the fragmentation and subsequent circularization of pieces of chromosomes. These “extrachromosomal circular DNAs” (ecDNAs) have long been known as “double minutes” for their appearance in metaphase spreads and by the lack of centromeric sequences. In the past few years renewed interest in this class of cancer-associated chromosomal rearrangements has been fueled by technological advances and by the realization that, due to their random segregation at mitosis, ecDNAs can accelerate tumor evolution, mediate drug resistance, and generally promote a more aggressive phenotype. Despite substantial progress, however, several key questions regarding the biology of ecDNAs, their dynamics during the early stages of tumor formation, and their contribution to tumor initiation and progression, remain unanswered. This is in part due to the lack of effective means to engineer and track ecDNAs in normal cells and in model organisms. Our group has extensive expertise in the generation and characterization of germline and somatic mouse models of human cancers, and we have pioneered the use of somatic genome editing to engineer chromosomal rearrangements in mice. In this grant application, supported by strong preliminary data, we describe a novel general strategy to model ecDNAs in cells and in mice. We have already generated three new genetically engineered mouse strains in which the formation of ecDNAs containing the oncogenes most commonly amplified in human cancers can be induced in a temporally and spatially controlled manner. Using a similar strategy, we have also generated cell lines in which formation of specific ecDNAs can be induced and tracked non-invasively using fluorescent reporters and selectable markers. We propose to use these innovative tools and reagents to address the following key questions: 1) Can oncogenic ecDNAs initiate tumor formation and/or accelerate tumor progression and metastasis in vivo? 2) How do oncogenic ecDNAs respond to changes in intracellular and extracellular environment? 3) Are there mechanisms preventing ecDNA formation and propagation in primary cells? 4) Is the presence of ecDNAs in cancer cells associated with unique therapeutically actionable vulnerabilities? 5) Can ecDNAs be transmitted horizontally between cells?
摘要 由局部扩增介导的癌基因表达增加是癌基因转移的常见机制。 在人类癌症中的激活。已经描述了导致癌基因扩增的两种主要机制: 染色体扩增和非染色体扩增。后一种机制的特点是, 存在多个被认为起源于片段化的环状DNA拷贝, 随后染色体片段的环化。这些“染色体外环状DNA”(ecDNAs)具有 长期以来被称为“双分钟”,因为它们出现在中期铺展中, 序列的 在过去的几年里,对这类癌症相关的染色体重排重新产生了兴趣, 由于技术进步和认识到,由于它们在有丝分裂时的随机分离, 可加速肿瘤演变、介导耐药性,并且通常促进更具侵袭性的表型。 然而,尽管取得了实质性进展,但关于ecDNAs生物学的几个关键问题,它们的动力学, 在肿瘤形成的早期阶段,它们对肿瘤发生和发展的作用仍然存在, 无人回应这部分是由于缺乏有效的手段来工程化和跟踪正常细胞中的ecDNAs, 在模式生物中。 我们的团队在生殖系和体细胞小鼠模型的生成和表征方面拥有广泛的专业知识 我们率先使用体细胞基因组编辑来设计染色体, 小鼠中的重排。在这份资助申请中,我们通过强有力的初步数据,描述了一种新的 在细胞和小鼠中建立ecDNAs模型的一般策略。 我们已经培育了三种新的基因工程小鼠品系, 含有在人类癌症中最常扩增的癌基因的肿瘤细胞可以在时间上被诱导, 空间控制方式。使用类似的策略,我们还产生了细胞系,其中形成了 可以使用荧光报道分子和选择标记非侵入性地诱导和追踪特异性的ecDNAs。 我们建议使用这些创新工具和试剂来解决以下关键问题: 1)致癌ecDNAs能否在体内启动肿瘤形成和/或加速肿瘤进展和转移? 2)致癌ecDNAs如何响应细胞内外环境的变化? 3)是否存在阻止原代细胞中ecDNA形成和繁殖的机制? 4)癌细胞中存在的ecDNAs是否与独特的治疗上可行的弱点有关? 5)ecDNAs能在细胞间水平传递吗?

项目成果

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Andrea Ventura其他文献

Andrea Ventura的其他文献

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{{ truncateString('Andrea Ventura', 18)}}的其他基金

Investigating microRNA Function in Homeostasis, Regeneration and Cancer
研究 microRNA 在稳态、再生和癌症中的功能
  • 批准号:
    10678921
  • 财政年份:
    2020
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating microRNA Function in Homeostasis, Regeneration and Cancer
研究 microRNA 在稳态、再生和癌症中的功能
  • 批准号:
    10242920
  • 财政年份:
    2020
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating microRNA Function in Homeostasis, Regeneration and Cancer
研究 microRNA 在稳态、再生和癌症中的功能
  • 批准号:
    10407066
  • 财政年份:
    2020
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating the roles of lncRNAs in cancer and development
研究 lncRNA 在癌症和发育中的作用
  • 批准号:
    8882352
  • 财政年份:
    2014
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating the roles of lncRNAs in cancer and development
研究 lncRNA 在癌症和发育中的作用
  • 批准号:
    9062295
  • 财政年份:
    2014
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating the roles of lncRNAs in cancer and development
研究 lncRNA 在癌症和发育中的作用
  • 批准号:
    8760845
  • 财政年份:
    2014
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating the roles of lncRNAs in cancer and development
研究 lncRNA 在癌症和发育中的作用
  • 批准号:
    9266375
  • 财政年份:
    2014
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating the functions of the miR-17~92 family of oncogenic microRNA cluster
致癌microRNA簇miR-17~92家族功能的研究
  • 批准号:
    8034401
  • 财政年份:
    2010
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating the functions of the miR-17~92 family of oncogenic microRNA clusters
研究致癌 microRNA 簇的 miR-17~92 家族的功能
  • 批准号:
    9247341
  • 财政年份:
    2010
  • 资助金额:
    $ 56.67万
  • 项目类别:
Investigating the functions of the miR-17~92 family of oncogenic microRNA clusters
研究致癌 microRNA 簇的 miR-17~92 家族的功能
  • 批准号:
    10064603
  • 财政年份:
    2010
  • 资助金额:
    $ 56.67万
  • 项目类别:

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