Tissue Microenvironment ant Tumor Hotspots in Drosophila

项目摘要/摘要 在癌变过程中，转化的上皮细胞通过多步骤演变为恶性肿瘤。 转化的细胞获得使它们能够致癌并最终成为肿瘤的特征的过程 恶性的。尽管许多基因已被确定与癌细胞进展的不同阶段有关， 人们对肿瘤发生的最初步骤知之甚少，在这些步骤中，突变细胞偏离了牢固的组织。 不受控制的过度生长的微环境。 在这项提案中，我们将使用果蝇模型来解剖基因如何从内源组织 微环境有助于肿瘤的形成。这项工作是我们长期努力破译 控制上皮组织肿瘤发生早期步骤的分子和细胞机制。在我们的 利用果蝇翅膀成像盘分析保守的肿瘤抑制基因(NTSG) 模型系统中，我们在翼铰中找到了肿瘤总是起源的特定区域。在这些特定情况下 “肿瘤热点”，ntsG功能丧失(LOF)的亲肿瘤细胞从上皮的顶端脱落， 并通过利用内源性JAK-STAT炎症信号活性启动致瘤过度生长。在……里面 相反，在肿瘤冷点的前肿瘤细胞，翼袋区域，从基底部突出。 上皮层，并经历细胞凋亡。翼铰肿瘤热点区域显示了一个特定的和 坚固的基本结构，包括丰富的微管，缠绕的丝状足细胞网络，并紧密层叠 基底膜。这些特定区域中的上皮组织被假设为创建 “肿瘤热点”，一个有利的组织内部微环境，迫使亲肿瘤细胞从 并进入一个适合肿瘤形成的环境。在建议的研究中，我们会 确定特定组织的细胞结构特征、局部内在信号和差异细胞竞争 通过追求以下三个特定目标参与翼盘模型中肿瘤热点的形成： (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的发生；以及(3) 确定细胞竞争在翼盘肿瘤热点和冷点分化中的作用。 这三个具体目标是相互独立的，可以单独执行。它的意义 我们建议的研究的意义在于它们与肿瘤发生的早期阶段直接相关。给定 上皮细胞结构的保护、细胞竞争机制及其重要作用 炎症信号通路在各种类型的癌症中发挥作用，肿瘤的发生可能是从 在许多上皮组织中，通过类似的机制形成了“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 实际上，在细胞获得致癌突变后，肿瘤可以被诱发。

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.