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(PQ4) Quantitative and multiplexed analysis of gene function in cancer in vivo

(PQ4) Quantitative and multiplexed analysis of gene function in cancer in vivo
(PQ4)体内癌症基因功能的定量和多重分析
批准号:
10469407
负责人:
Dmitri Petrov
金额:
$44.64万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-01 至 2024-08-31

项目摘要

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中文摘要
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英文摘要
PROJECT SUMMARY Genome sequencing has catalogued the somatic alterations in human cancers and identified many putative driver genes. However, human cancers generally evolve through the sequential acquisition of multiple genomic alterations and simply identifying recurrent genomic alterations does not necessarily reveal their functional importance to cancer growth. Genetically engineered mouse models have become a mainstay for the analysis of gene function in cancer in vivo, however the breadth of their utility is limited by the fact that they are neither readily scalable nor sufficiently quantitative. To increase the scope and precision of in vivo cancer modeling, we previously integrated conventional genetically-engineered mouse models, CRISPR/Cas9-based somatic genome engineering, and quantitative genomics with mathematical approaches. We developed methods to inactivate multiple genes in parallel in mouse models of lung cancer using pools of barcoded sgRNA- containing lentiviral vectors. This tumor barcoding with sequencing (Tuba-seq) approach uncovers the size of each tumor, enables the parallel investigation of multiple tumor genotypes in individual mice, and allows the generation of large-scale maps of gene function within autochthonous cancer models. Our preliminary data and novel genetic systems, as well as our dedicated and collaborative team of investigators with expertise in cancer genetics, mouse models, genome-editing, clinical cancer care, and quantitative modeling make us uniquely positioned to conduct these studies. In this proposal, we will extend Tuba-seq to quantify the effect of combinatorial genetic alterations through the development and validation of a platform for the rapid and quantitative analysis of interactions between genetic alterations on tumor growth in vivo. To enable multiplexed and quantitative analysis of the impact of temporally controlled genomic alterations on cancer cell growth in vivo, we will also develop a system for inducible genome editing in established lung tumors. Finally, we will develop novel in vivo approaches to comprehensively and broadly uncover the gene expression programs in cancer cells of different genotypes in parallel. Through multiplexed in vivo genetic alterations, the effect of putative cancer drivers can be uncovered at an unprecedented scale and resolution. The results of this proposal will be significant because innovative methods for the cost-effective, quantitative, and multiplexed analysis of the genetic determinants of cancer pathogenesis will illuminate novel aspects of tumorigenesis and accelerate our ability to understand cancer evolution, drug responses, and therapy resistance.
期刊论文(5)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1084/jem.20221472
发表时间: 2023-06-05
期刊: The Journal of experimental medicine
影响因子: --
作者: []
通讯作者:
DOI: 10.1158/0008-5472.can-21-0716
发表时间: 2021-09-01
期刊: Cancer research
影响因子: 11.2
作者: [Li C, Lin WY, Rizvi H, Cai H, McFarland CD, Rogers ZN, Yousefi M, Winters IP, Rudin CM, Petrov DA, Winslow MM]
通讯作者: Winslow MM
DOI: 10.1016/j.crmeth.2022.100295
发表时间: 2022-09-19
期刊: Cell reports methods
影响因子: --
作者: []
通讯作者:
DOI: 10.1101/cshperspect.a041382
发表时间: 2023-06
期刊: Cold Spring Harbor perspectives in medicine
影响因子: 5.4
作者: [Yuning J. Tang;Emily G. Shuldiner;S. Karmakar;M. Winslow]
通讯作者: Yuning J. Tang;Emily G. Shuldiner;S. Karmakar;M. Winslow
Unraveling mechanisms of tumor suppression in lung cancer
  • 批准号:
    10633103
  • 项目类别:
  • 资助金额:
    $43.12万
  • 财政年份:
    2019
  • 负责人:
    Dmitri Petrov
  • 依托单位:
Unraveling mechanisms of tumor suppression in lung cancer
  • 批准号:
    10164612
  • 项目类别:
  • 资助金额:
    $49.07万
  • 财政年份:
    2019
  • 负责人:
    Dmitri Petrov
  • 依托单位:
Unraveling mechanisms of tumor suppression in lung cancer
  • 批准号:
    10405507
  • 项目类别:
  • 资助金额:
    $46.85万
  • 财政年份:
    2019
  • 负责人:
    Dmitri Petrov
  • 依托单位:
(PQ4) Quantitative and multiplexed analysis of gene function in cancer in vivo
  • 批准号:
    10238887
  • 项目类别:
  • 资助金额:
    $46.2万
  • 财政年份:
    2018
  • 负责人:
    Dmitri Petrov
  • 依托单位:
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