Tissue Microenvironment ant Tumor Hotspots in Drosophila

果蝇组织微环境蚂蚁肿瘤热点

基本信息

  • 批准号:
    10237130
  • 负责人:
  • 金额:
    $ 34.77万
  • 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:
    2019-06-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY / ABSTRACT During carcinogenesis, transformed epithelial cells evolve into a malignant neoplasm through a multistep process, whereby the transformed cells acquire traits that enable them to become tumorigenic and ultimately malignant. Although many genes have been identified as involved in different steps of cancer-cell progression, little is known of the initial steps of tumorigenesis, wherein mutant cells deviate from the robustly organized microenvironment to undergo uncontrolled overgrowth. In this proposal we will use the Drosophila model to dissect genetically how endogenous tissue microenvironment contributes to tumor formation. This work is part of our long-term effort in deciphering the molecular and cellular mechanisms that govern the early steps of tumorigenesis in epithelial tissues. In our analysis of conserved neoplastic tumor-suppressor genes (nTSGs) using the Drosophila wing imaginal disc model system, we found specific regions in the wing hinge in which tumors always originate. In these specific “tumor hotspots,” nTSG loss-of-function (LOF) pro-tumor cells delaminate from the apical side of the epithelium, and start tumorigenic overgrowth by exploiting endogenous JAK-STAT inflammatory signaling activity. In contrast, the pro-tumor cells in tumor coldspots, the wing pouch area, are extruded from the basal side of the epithelial layer and undergo apoptosis. The wing hinge tumor hotspot area displays a network of specific and robust basal structures, including enriched microtubules, a web of intertwining filopodia, and tightly laminated basement membranes. The epithelial organization in these specific regions is hypothesized to create the “tumor hotspot”, a favorable tissue-intrinsic microenvironment, which forces pro-tumor cells to delaminate from the epithelial layer and enter an environment that is suitable for tumorigenesis. In the proposed studies, we will determine how specific tissue cytoarchitectural traits, local intrinsic signaling and differential cell competition are involved in tumor hotspot formation in the wing disc model by pursuing the following three specific aims: (1) To determine how cytoarchitectural structures regulate the delamination direction of pro-tumor cells in tumor hotspots; (2) To determine how JAK-STAT signaling is involved in hotspot tumorigenesis; and (3) To determine the role of cell competition in tumor hotspot and coldspot differentiation in the wing disc. These three specific aims are independent from each other and can be executed separately. The significance of our proposed studies lies in their implications directly related to early stages of tumorigenesis. Given the conservation of the epithelial cytoarchitectural structures, cell competition mechanisms and the significant role inflammatory signaling pathways play during various types of cancer, tumorigenesis is likely to be initiated from “tumor hotspots” by a similar mechanism in many epithelial tissues. Understanding these regulatory mechanisms will therefore provide new insights into how tissue-intrinsic microenvironment determines whether tumors can actually be induced after cells acquiring cancer-promoting mutations.
项目总结/摘要 在癌变过程中,转化的上皮细胞通过多步骤转化为恶性肿瘤。 过程,由此转化的细胞获得使其成为致瘤性的性状,并最终 恶性的尽管许多基因已被鉴定为参与癌细胞进展的不同步骤, 肿瘤发生的初始步骤知之甚少,其中突变细胞偏离了稳健组织的细胞。 微环境经历不受控制的过度生长。 在这个建议中,我们将使用果蝇模型来解剖遗传学上内源性组织是如何 微环境有助于肿瘤的形成。这项工作是我们长期努力破译 控制上皮组织中肿瘤发生的早期步骤的分子和细胞机制。在我们 利用果蝇翅成虫盘分析保守的肿瘤抑制基因(nTSGs) 在模型系统中,我们发现了肿瘤总是起源于翼铰链的特定区域。在这些具体 “肿瘤热点”,nTSG功能丧失(LOF)促肿瘤细胞从上皮的顶侧分层, 并通过利用内源性JAK-STAT炎症信号传导活性启动致瘤性过度生长。在 相比之下,在肿瘤冷点(翅囊区域)中的促肿瘤细胞从基底侧挤出。 上皮层并经历细胞凋亡。翼铰链肿瘤热点区域显示了一个特异性和 坚固的基底结构,包括丰富的微管,相互缠绕的丝状伪足网,以及紧密的层压结构。 基底膜这些特定区域的上皮组织被假设为创造了 “肿瘤热点”是一种有利的组织内在微环境,它迫使促肿瘤细胞从 上皮层并进入适合肿瘤发生的环境。在建议的研究中,我们会 确定特定组织细胞结构特征、局部内在信号传导和差异细胞竞争 通过追求以下三个特定目标参与翼盘模型中的肿瘤热点形成: (1)为了确定细胞结构如何调节前肿瘤细胞的分层方向, 肿瘤热点;(2)确定JAK-STAT信号传导如何参与热点肿瘤发生;和(3) 确定翼盘中肿瘤热点和冷点分化中细胞竞争的作用。 这三个具体目标是相互独立的,可以分开执行。意义 我们提出的研究的重点在于它们与肿瘤发生的早期阶段直接相关。鉴于 保护上皮细胞结构,细胞竞争机制和重要作用 炎症信号通路在各种类型的癌症中起作用,肿瘤发生可能是由 在许多上皮组织中通过类似的机制形成“肿瘤热点”。了解这些法规 因此,机制将为组织内在微环境如何决定 在细胞获得促癌突变后实际上可以诱发肿瘤。

项目成果

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Wu-Min Deng其他文献

Wu-Min Deng的其他文献

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{{ truncateString('Wu-Min Deng', 18)}}的其他基金

Tissue Microenvironment ant Tumor Hotspots in Drosophila
果蝇组织微环境蚂蚁肿瘤热点
  • 批准号:
    9904581
  • 财政年份:
    2019
  • 资助金额:
    $ 34.77万
  • 项目类别:
Tissue Microenvironment ant Tumor Hotspots in Drosophila
果蝇组织微环境蚂蚁肿瘤热点
  • 批准号:
    10684153
  • 财政年份:
    2019
  • 资助金额:
    $ 34.77万
  • 项目类别:
Tissue Microenvironment ant Tumor Hotspots in Drosophila
果蝇组织微环境蚂蚁肿瘤热点
  • 批准号:
    10475031
  • 财政年份:
    2019
  • 资助金额:
    $ 34.77万
  • 项目类别:
Mechanistic investigation of malignant rhabdoid childhood tumor using the Drosophila model
使用果蝇模型研究恶性横纹肌样儿童肿瘤的机制
  • 批准号:
    10459446
  • 财政年份:
    2018
  • 资助金额:
    $ 34.77万
  • 项目类别:
Mechanistic investigation of malignant rhabdoid childhood tumor using the Drosophila model
使用果蝇模型研究恶性横纹肌样儿童肿瘤的机制
  • 批准号:
    10012781
  • 财政年份:
    2018
  • 资助金额:
    $ 34.77万
  • 项目类别:
Mechanistic investigation of malignant rhabdoid childhood tumor using the Drosophila model
使用果蝇模型研究恶性横纹肌样儿童肿瘤的机制
  • 批准号:
    10215434
  • 财政年份:
    2018
  • 资助金额:
    $ 34.77万
  • 项目类别:
Intercellular Communication and Oocyte Polarity
细胞间通讯和卵母细胞极性
  • 批准号:
    7995813
  • 财政年份:
    2010
  • 资助金额:
    $ 34.77万
  • 项目类别:
Notch signaling and germline-soma interactions in the Drosophila ovarian model
果蝇卵巢模型中的Notch信号传导和种系-体细胞相互作用
  • 批准号:
    10467652
  • 财政年份:
    2006
  • 资助金额:
    $ 34.77万
  • 项目类别:
Notch signaling and germline-soma interactions in the Drosophila ovarian model
果蝇卵巢模型中的Notch信号传导和种系-体细胞相互作用
  • 批准号:
    10801363
  • 财政年份:
    2006
  • 资助金额:
    $ 34.77万
  • 项目类别:
Intercellular Communication and Oocyte Polarity
细胞间通讯和卵母细胞极性
  • 批准号:
    8447316
  • 财政年份:
    2006
  • 资助金额:
    $ 34.77万
  • 项目类别:

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由actomyosin介导的集体性细胞迁移对唇腭裂发生的影响的研究
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Nuclear force feedback as rheostat for actomyosin tension control
核力反馈作为肌动球蛋白张力控制的变阻器
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    2024
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CAREER: Cytokinesis without an actomyosin ring and its coordination with organelle division
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