Developmental Mechanisms Driving Cell Invasion in Pediatric Brain Cancers

项目总结-亨茨曼癌症研究所，罗德尼斯图尔特 胚胎形态发生机制在人类癌症，特别是儿童脑肿瘤中经常被激活 肿瘤的特别地，调节神经嵴（NC）上皮细胞向间质细胞转化（EMT）和细胞增殖的基因， 迁移，如转录因子的Snail家族，通常在肿瘤细胞中被重新激活，以促进肿瘤细胞的增殖。 通过改变细胞粘附、细胞骨架、细胞凋亡和 信号分子这导致增强的肿瘤细胞传播、自我更新和化学抗性， 这种毁灭性的组合会导致治疗失败和癌症相关的死亡率。的长期目标 这项研究是为了确定胚胎EMT程序的基本，保守和限速效应， 推动癌症进展，以确定可单独使用或联合使用的新靶点和治疗方法。 与目前的治疗方法结合以消除肿瘤细胞。本项目的总体目标， 代表了我们实现长期目标的下一个合乎逻辑的步骤，是1）使用强大的遗传属性， 斑马鱼系统，以确定驱动NC EMT和细胞迁移的新机制，以及2）确定是否抑制 儿科脑肿瘤模型中的一种或多种EMT效应物防止肿瘤侵袭和/或扩散。 核心假设是细胞粘附、细胞骨架和/或信号分子的子集是必需的 用于执行NC EMT，并且这些分子代表了抑制EMT诱导的脑 肿瘤侵袭。根据已发表的和初步的数据，这一假设将通过以下三个方面进行检验： 具体目标是：1）确定高度保守的Foxd 3转录因子是否直接控制 EMT期间Snail基因的表达，2）鉴定EMT期间Foxd 3/Snail依赖性EMT的基本效应子。 NC发展和3）确定体内脑肿瘤侵袭是否需要一种或多种NC效应物。 该提案具有创新性，因为它采用了新的遗传和成像技术来动态测量 并操纵发育EMT程序在整个动物脑肿瘤侵袭过程中的影响， 首次实现单细胞分辨率，从而能够快速识别新的脑靶点和治疗方法。 癌的成功完成拟议的研究将产生重大影响，因为它是 预计将垂直推进和扩大我们对如何操纵发展EMT的理解 在许多疾病环境中的计划，包括NC衍生的出生缺陷，纤维化和癌症侵袭， 从而允许对这些疾病进行有效治疗的战略设计。

PROJECT SUMMARY – HUNTSMAN CANCER INSTITUTE, RODNEY STEWART Embryonic morphogenesis mechanisms are frequently activated in human cancers, particularly childhood brain tumors. In particular, genes that regulate neural crest (NC) epithelial-to-mesenchymal transition (EMT) and cell migration, such as the Snail family of transcription factors, are often re-activated in tumor cells to promote malignant progression by changing the available repertoire of cell adhesion, cytoskeletal, apoptotic and signaling molecules. This leads to enhanced tumor-cell dissemination, self-renewal and chemo-resistance, a devastating combination that promotes treatment failure and cancer-related mortality. The long-term goal of this research is to define the essential, conserved and rate-limiting effectors of embryonic EMT programs that drive cancer progression in order to identify new targets and therapeutics that can be used alone or in conjunction with current therapeutics to eliminate tumor cells. The overall objective of the current project, which represents the next logical step toward our long-term goal, is to 1) use the powerful genetic attributes of the zebrafish system to identify new mechanisms driving NC EMT and cell migration and 2) determine if inhibiting one or more EMT effectors in a model of pediatric brain tumors prevents tumor invasion and/or dissemination. The central hypothesis is that a subset of cell adhesion, cytoskeleton and/or signaling molecules are essential for executing NC EMT and that these molecules represent promising targets to inhibit EMT-induced brain tumor invasion. Guided by published and preliminary data, this hypothesis will be tested by pursuing three specific aims in which we will: 1) determine if the highly conserved Foxd3 transcription factor directly controls the expression of Snail genes during EMT, 2) identify essential effectors of Foxd3/Snail-dependent EMT during NC development and 3) determine if one or more NC effectors are required for brain tumor invasion in vivo. The proposal is innovative because it employs new genetic and imaging technologies to dynamically measure and manipulate the impact of developmental EMT programs during brain tumor invasion in whole animals at single-cell resolution for the first time, allowing the rapid identification of new targets and therapeutics for brain cancers. The successful completion of the proposed research will have a significant impact because it is expected to vertically advance and expand our understanding of how to manipulate developmental EMT programs in a number of disease settings, including NC-derived birth defects, fibrosis and cancer invasion, thus allowing for the strategic design of effective treatments for these diseases.