Organoid modeling to determine and reverse age-related epigenetic changes contributing to risk of colorectal cancer

用于确定和逆转导致结直肠癌风险的年龄相关表观遗传变化的类器官建模

基本信息

  • 批准号:
    10657739
  • 负责人:
  • 金额:
    $ 40.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-07-01 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

There is great need to develop systems in which the course for initiation and progression of cancer, and therapies directed at these steps can be studied directly in mouse and human cells, and over time courses relevant to real world tumorigenesis. While engineered mouse models are valuable, there is a need to develop complementary systems where meaningful, relatively rapid in-vitro work can yield substantial pre-clinical insights leading to final animal testing. In this regard, we have developed an organoid model which is yielding important data for studying the age-related risks for developing colorectal cancer (CRC). The studies build on extensive data, now just in press, derived from mouse organoids from normal proximal colon wherein we have modeled key steps in the initiation and progression of CRC. The key findings are that despite the organoids being genetically stable over time, they evolve an abnormal, gene promoter CpG island phenotype (CIMP) during long periods of growth. This pattern is very similar to changes seen with aging in normal human colon and which parallels the increasing CRC risk with age. CIMP involves repression of associated gene expression, and/or perhaps even more importantly affects inducibility of genes which otherwise normally function in a feedback fashion to blunt abnormal WNT and other stem pathway activation, prevent abnormal retention of cell renewal, and induce differentiation. In this context, induction of Braf mutations in the older versus younger organoids result in a much more rapid evolution of autonomous Wnt pathway activation, stem cell versus differentiation features and one-step transformation by oncogenic Braf. The resulting cancers have typical histologic features and the epigenetic abnormality of CIMP resembling oncogenic BRAF-driven human proximal colon CRCs. Critically, CRISPR- mediated simultaneous inactivation of multiple CIMP target genes in young organoids rapidly converts these to the old organoid phenotype, importantly resulting in rapid one-step transformation by oncogenic Braf. In the current proposal, we will determine the role of genes affected by age-related CIMP in driving human CRC in the context of KRAS, BRAF and APC mutations, thus addressing the epigenetic dependency of ~75% of CRC evolution. This includes extrapolating our studies to human colon organoids. Importantly, our unique models provide a novel setting to test whether epigenetic therapies can alter the above evolution of CIMP to suppress age-related changes, which may otherwise enhance CRC risk. Results from these studies may allow insights for strategies to prevent and/or intercept CRC evolution. All of the work in our proposal has potential to define management strategies for CRC prevention and interception, which could prove especially valuable for decreasing CRC risk in individuals harboring familial germ line predisposition to colon polyps and for patients with inflammatory bowel diseases.
非常需要开发一种系统,在这种系统中癌症的发生和发展过程以及治疗方法 针对这些步骤,可以直接在小鼠和人类细胞中研究,并随着时间的推移而与现实相关 世界肿瘤发生学。虽然转基因小鼠模型很有价值,但仍有必要开发补充 有意义的、相对快速的体外工作可以产生实质性的临床前洞察力的系统 动物实验。在这方面,我们开发了一个有机模型,该模型正在为研究提供重要的数据 患结直肠癌(CRC)的年龄相关风险。这些研究建立在大量数据的基础上,这些数据现在刚刚发布 按,从正常近端结肠的小鼠器官派生而来,我们模拟了 儿童权利公约的启动和进展。关键的发现是,尽管有机化合物在基因上是稳定的 随着时间的推移,它们在长期的生长过程中会进化出一种异常的基因启动子CpG岛表型(CIMP)。这 这种模式非常类似于正常人结肠随年龄增长而出现的变化,并与不断增加的 结直肠癌发病风险随年龄增长而增加。CIMP涉及相关基因表达的抑制,和/或甚至更多 重要地影响基因的诱导性,否则这些基因以反馈的方式发挥作用以钝化异常 WNT等干细胞通路激活,防止细胞更新异常滞留,诱导分化。 在这种情况下,在较老的与较年轻的有机体中诱导BRAF突变会导致更快的 自主Wnt途径激活、干细胞与分化特征及一步法的演变 致癌的BRAF的转化。由此产生的癌症具有典型的组织学特征和表观遗传学 类似于致癌性BRAF驱动的人类近端结肠CRCs的CIMP异常。关键的是,CRISPR- 在年轻的器官中介导的多个CIMP靶基因的同时失活迅速将这些转化为 旧的有机物表型,重要的是导致致癌的BRAF快速一步转化。在 目前的建议,我们将确定年龄相关CIMP影响的基因在驱动人类结直肠癌中的作用 KRAS、BRAF和APC突变的背景,从而解决了~75%的结直肠癌的表观遗传依赖性 进化论。这包括将我们的研究外推到人类结肠有机化合物。重要的是,我们独特的模式 提供了一种新的环境来测试表观遗传疗法是否可以改变CIMP的上述进化以抑制 与年龄相关的变化,否则可能会增加结直肠癌的风险。这些研究的结果可能会让人们对 防止和/或拦截CRC演变的战略。 我们提案中的所有工作都有可能定义CRC预防和管理战略 拦截,这可能被证明对降低携带家族细菌的个人的结直肠癌风险特别有价值 易患结肠息肉和炎症性肠病患者。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Combining EZH2 and HDAC inhibitors to target castration-resistant prostate cancers.
  • DOI:
    10.1371/journal.pbio.3002081
  • 发表时间:
    2023-04
  • 期刊:
  • 影响因子:
    9.8
  • 作者:
    Coulter, Jonathan B.;Easwaran, Hariharan
  • 通讯作者:
    Easwaran, Hariharan
Genetic and epigenetic dependencies in colorectal cancer development.
  • DOI:
    10.1093/gastro/goac035
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    3.6
  • 作者:
    Parmar, Sehej;Easwaran, Hariharan
  • 通讯作者:
    Easwaran, Hariharan
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STEPHEN B. BAYLIN其他文献

STEPHEN B. BAYLIN的其他文献

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{{ truncateString('STEPHEN B. BAYLIN', 18)}}的其他基金

Epigenetic Therapies - New Approaches
表观遗传疗法 - 新方法
  • 批准号:
    10696160
  • 财政年份:
    2021
  • 资助金额:
    $ 40.72万
  • 项目类别:
Epigenetic Therapies - New Approaches
表观遗传疗法 - 新方法
  • 批准号:
    10269639
  • 财政年份:
    2021
  • 资助金额:
    $ 40.72万
  • 项目类别:
Epigenetic Therapies - New Approaches
表观遗传疗法 - 新方法
  • 批准号:
    10470361
  • 财政年份:
    2021
  • 资助金额:
    $ 40.72万
  • 项目类别:
Organoid modeling to determine and reverse age-related epigenetic changes contributing to risk of colorectal cancer
用于确定和逆转导致结直肠癌风险的年龄相关表观遗传变化的类器官建模
  • 批准号:
    10206053
  • 财政年份:
    2019
  • 资助金额:
    $ 40.72万
  • 项目类别:
Characterizing age-associated epigenetic alterations and their roles in tumor development
表征与年龄相关的表观遗传改变及其在肿瘤发展中的作用
  • 批准号:
    9926803
  • 财政年份:
    2019
  • 资助金额:
    $ 40.72万
  • 项目类别:
Organoid modeling to determine and reverse age-related epigenetic changes contributing to risk of colorectal cancer
用于确定和逆转导致结直肠癌风险的年龄相关表观遗传变化的类器官建模
  • 批准号:
    10457265
  • 财政年份:
    2019
  • 资助金额:
    $ 40.72万
  • 项目类别:
(PQ4) - Tools for simultaneous disruption of multiple epigenetically silenced genes for studying their roles in tumorigenesis using ex vivo human and mouse colon organoid and in vivo mouse models
(PQ4) - 同时破坏多个表观遗传沉默基因的工具,用于使用离体人类和小鼠结肠类器官以及体内小鼠模型研究它们在肿瘤发生中的作用
  • 批准号:
    10471240
  • 财政年份:
    2018
  • 资助金额:
    $ 40.72万
  • 项目类别:
Epigenetic Drivers of Cancer (PQ 10)
癌症的表观遗传驱动因素 (PQ 10)
  • 批准号:
    8538911
  • 财政年份:
    2012
  • 资助金额:
    $ 40.72万
  • 项目类别:
Epigenetic Drivers of Cancer (PQ 10)
癌症的表观遗传驱动因素 (PQ 10)
  • 批准号:
    9039821
  • 财政年份:
    2012
  • 资助金额:
    $ 40.72万
  • 项目类别:
Epigenetic Drivers of Cancer (PQ 10)
癌症的表观遗传驱动因素 (PQ 10)
  • 批准号:
    8384811
  • 财政年份:
    2012
  • 资助金额:
    $ 40.72万
  • 项目类别:

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