Microbiome-triggered reprogramming and mutation of colon epithelial cells leading to tumor stem-like cells

微生物触发结肠上皮细胞重编程和突变,形成肿瘤干样细胞

基本信息

  • 批准号:
    9901474
  • 负责人:
  • 金额:
    $ 49.31万
  • 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:
    2019-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Colorectal cancer is the third leading cause of cancer with more than half of cases occurring in advanced stages that are difficult to cure. New prevention strategies are needed. The colonic microbiome plays an important role in the etiology of colorectal cancer (CRC). Our laboratory has studied Enterococcus faecalis in models of inflammation-associated CRC. This human commensal can polarize (or activate) macrophages to reprogram and transform epithelial cells into cancer cells. This process is referred to as the “microbiome-induced bystander effect.” In CRC, tumor stem-like cells are believed to originate from stem cells at the base of crypts. However, newer data supports fully differentiated epithelial cells at the top of crypts as cells of origin for CRC. This fits with a “top-down” model of morphogenesis for human colon adenomas in which transformed stem-like cells expand downward to replace normal crypt structures. In this project, we hypothesize that microbiome-polarized colon macrophages cause mutagenesis and reprogramming of differentiated epithelial cells in the upper portion of crypts toward pluripotency and stemness, thereby driving malignant transformation. Using established in vitro and in vivo models for microbiome-triggered and macrophage-induced malignant transformation, we will assess differentiated colon epithelial cells for reprogramming and mutation during transfor- mation into tumor stem-like cells. Mutations in key driver genes along with genome-wide changes in chromosomes, gene expression, and methylation will be assessed to establish the sequence of events during reprogramming and transformation. Finally, transformed malignant clones will be enriched by organoid culture and allografts characterized in immunodeficient mice. The preventive effect of probiotics (Lactobacillus and Bifidobacterium) on a microbiome- induced bystander effect will also be assessed. Using these same in vitro and in vivo models, the role of signaling by tumor necrosis factor alpha as a key mediator for the microbiome- induced bystander effect will be assessed. We hypothesize that blocking a receptor for tumor necrosis factor alpha will lead to downregulation of a functional tumor stem-like cell marker, doublecortin-like kinase 1, and thereby prevent microbiome-driven colon carcinogenesis. These experiments will help determine how intestinal commensals polarize innate immune cells to produce bystander effects and thereby induce mutagenesis, reprogramming and transformation of colon epithelial cells. Finally, we will investigate whether probiotics can inhibit microbiome- driven carcinogenesis and thereby bolster this as an approach to CRC prevention.
结直肠癌是第三大致癌原因,超过一半的病例发生在 难以治愈的晚期。需要新的预防策略。结肠 微生物组在结直肠癌的病因学中起着重要作用。我们的实验室 研究了炎症性结直肠癌模型中的粪肠球菌。这个人类 共生能极化(或激活)巨噬细胞以重新编程和转化上皮细胞 转化成癌细胞。这个过程被称为“微生物群诱导的旁观者效应”。在……里面 CRC,肿瘤干细胞样细胞被认为起源于隐窝底部的干细胞。 然而,较新的数据支持在隐窝顶部完全分化的上皮细胞作为 CRC的由来。这符合人类结肠腺瘤的“自上而下”的形态发生模型。 在这种情况下,转化的干细胞向下扩张,以取代正常的隐窝结构。在这 项目中,我们假设微生物组极化的结肠巨噬细胞导致突变和 隐窝上部分化上皮细胞向多能性方向的重编程 和茎,从而推动恶性转化。利用在体外和体内建立的 微生物组触发和巨噬细胞诱导的恶性转化模型,我们将 评估分化的结肠上皮细胞在移植过程中的重编程和突变 转化为肿瘤干细胞。关键驱动基因的突变以及全基因组 将评估染色体、基因表达和甲基化的变化,以确定 重新编程和转换期间的事件顺序。最后,转化为恶性的 克隆将通过器官培养和具有免疫缺陷特征的同种异体移植物来丰富 老鼠。益生菌(乳杆菌和双歧杆菌)对一种微生物群的预防作用 还将评估诱导的旁观者效应。使用这些相同的体外和体内模型, 肿瘤坏死因子α作为微生物组关键介体的信号转导作用 将对诱导的旁观者效应进行评估。我们假设阻断肿瘤的受体 坏死因子α将导致一种功能性肿瘤干细胞标记物的下调, Doublectin-like kinase1,从而防止微生物群驱动的结肠癌发生。这些 实验将有助于确定肠道共生体如何极化先天免疫细胞以 产生旁观者效应,从而诱导突变、重新编程和转化 结肠上皮细胞。最后,我们将调查益生菌是否可以抑制微生物群- 促进致癌,从而将其作为预防结直肠癌的一种方法。

项目成果

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MARK M HUYCKE其他文献

MARK M HUYCKE的其他文献

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{{ truncateString('MARK M HUYCKE', 18)}}的其他基金

Microbiome-triggered reprogramming and mutation of colon epithelial cells leading to tumor stem-like cells
微生物触发结肠上皮细胞重编程和突变,形成肿瘤干样细胞
  • 批准号:
    10368086
  • 财政年份:
    2019
  • 资助金额:
    $ 49.31万
  • 项目类别:
Microbiome-triggered reprogramming and mutation of colon epithelial cells leading to tumor stem-like cells
微生物触发结肠上皮细胞重编程和突变,形成肿瘤干样细胞
  • 批准号:
    10589872
  • 财政年份:
    2019
  • 资助金额:
    $ 49.31万
  • 项目类别:
Enterococcus faecalis, Colorectal Cancer, and Bystander Effects
粪肠球菌、结直肠癌和旁观者效应
  • 批准号:
    7821205
  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
  • 项目类别:
Enterococcus faecalis, Colorectal Cancer, and Bystander Effects
粪肠球菌、结直肠癌和旁观者效应
  • 批准号:
    7525511
  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
  • 项目类别:
Enterococcus faecalis, Colorectal Cancer, and Bystander Effects
粪肠球菌、结直肠癌和旁观者效应
  • 批准号:
    8268533
  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
  • 项目类别:
Enterococcus faecalis, Colorectal Cancer, and Bystander Effects
粪肠球菌、结直肠癌和旁观者效应
  • 批准号:
    7637796
  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
  • 项目类别:
Enterococcus faecalis, Colorectal Cancer, and Bystander Effects
粪肠球菌、结直肠癌和旁观者效应
  • 批准号:
    8069855
  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
  • 项目类别:

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新型同种异体骨软骨移植联合生长因子-胶原蛋白结合域融合技术的建立
  • 批准号:
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    $ 49.31万
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复合同种异体移植促进角膜移植的存活
  • 批准号:
    7878675
  • 财政年份:
    2009
  • 资助金额:
    $ 49.31万
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Composite Allografting for Promoting Survival of Corneal Transplants
复合同种异体移植促进角膜移植的存活
  • 批准号:
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  • 财政年份:
    2009
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  • 批准号:
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  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
  • 批准号:
    8010394
  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
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    8208131
  • 财政年份:
    2008
  • 资助金额:
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
  • 批准号:
    7575273
  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
  • 项目类别:
Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
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    7765518
  • 财政年份:
    2008
  • 资助金额:
    $ 49.31万
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