Tissue Microenvironment ant Tumor Hotspots in Drosophila

果蝇组织微环境蚂蚁肿瘤热点

• 批准号: 10684153
• 负责人: Wu-Min Deng
• 金额: $ 34.07万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10684153
• 关键词: Acetylation; Actomyosin; Address; Ants; Apical; Apoptosis; Area; Basement membrane; Biological Assay; Biological Models; Candidate Disease Gene; Cell physiology; Cells; Collaborations; Drosophila genus; Environment; Epithelial Cells; Epithelium; Exposure to; Extracellular Matrix; Filopodia; Gene Mutation; Genes; Genetic; Genetic Epistasis; Growth; Growth Associated Protein 43; HDAC6 gene; Inflammatory; Internet; Malignant - descriptor; Malignant Neoplasms; Measures; Mechanical Stress; Mechanics; Mediating; Microtubules; Modeling; Modification; Molecular; Mutation; Outcome; Play; Process; Protein-Lysine 6-Oxidase; Research; Role; Side; Signal Pathway; Signal Transduction; Spottings; Structure; Technology; Testing; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Wing; Work; cancer type; carcinogenesis; cell transformation; experimental study; genetic manipulation; imaginal disc; insight; loss of function; mutant; neoplastic; neoplastic cell; trait; tumor; tumor initiation; tumorigenesis; tumorigenic; uncontrolled cell growth

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.

项目摘要 /摘要 在癌变期间，转化的上皮细胞通过多步骤演变成恶性肿瘤 过程，转化的细胞获得特征，使它们能够变成肿瘤性并最终 尽管许多基因已被鉴定为癌细胞进展的不同步骤，但 肿瘤发生的初始步骤知之甚少，其中突变细胞偏离了牢固组织的 微环境会经历不受控制的过度生长。 在此提案中，我们将使用果蝇模型剖析一般的内源性组织 微环境有助于形成肿瘤。这项工作是我们为破译的长期努力的一部分 分子和细胞机制控制上皮组织中肿瘤发生的早期步骤。在我们的 使用果蝇翼盘分析保守的肿瘤 - 抑制基因（NTSG） 模型系统，我们发现肿瘤始终起源的机翼铰链中的特定区域。在这些特定的情况下 “肿瘤热点”，NTSG功能丧失（LOF）亲肿瘤细胞从上皮的顶端分层， 并通过利用内源性JAK-STAT炎症信号传导活性来开始肿瘤过度生长。在 对比度，肿瘤冷点中的亲肿瘤细胞，翼袋区域被从基本侧挤出 上皮层并经历凋亡。机翼铰链肿瘤热点区域显示一个特定的网络和 强大的基本结构，包括富集的微管，一个相互交织的丝状结构，并紧密地层压 地下室机制。假设这些特定区域的上皮组织以创建 “肿瘤热点”，一种有利的组织中微环境，迫使亲肿瘤细胞从 上皮层并进入适合肿瘤发生的环境。在拟议的研究中，我们将 确定特定的组织细胞结构特征，局部固有信号传导和差异细胞竞争 通过追求以下三个特定目的，参与机翼盘模型中的肿瘤热点形成： （1）确定细胞结构如何调节亲肿瘤细胞的分层方向 肿瘤热点； （2）确定jak-stat信号如何参与热点肿瘤发生； （3）到 确定细胞竞争在肿瘤热点和机翼盘中的冷点分化中的作用。 这三个特定目标彼此独立，可以单独执行。意义 我们提出的研究在于它们的含义与肿瘤发生的早期阶段直接相关。鉴于 保护上皮细胞结构结构，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期间都可以发挥作用，肿瘤发生可能会从 许多上皮组织中类似机制的“肿瘤热点”。了解这些监管 因此，机制将提供有关组织中微环境如何决定是否确定是否是否确定的新见解 实际上可以在促进癌症突变的细胞后诱导肿瘤。