Developmental Mechanisms Driving Cell Invasion in Pediatric Brain Cancers

项目摘要-洪博培癌症研究所，罗德尼·斯图尔特 胚胎形态发生机制在人类癌症中经常被激活，特别是在儿童脑中 肿瘤。特别是，调节神经脊(NC)上皮向间充质转化(EMT)和细胞的基因 迁移，如Snail家族的转录因子，经常在肿瘤细胞中被重新激活以促进 通过改变现有的细胞黏附、细胞骨架、细胞凋亡和 信号分子。这会导致肿瘤细胞扩散、自我更新和抗药性增强，a 导致治疗失败和癌症相关死亡率的毁灭性组合。的长期目标是 本研究旨在定义胚胎EMT计划的基本的、保守的和限速的效应器 推动癌症进展，以确定新的靶点和治疗方法，可单独使用或在 与当前的治疗方法相结合以消除肿瘤细胞。当前项目的总体目标，即 代表着朝着我们的长期目标迈出的合乎逻辑的下一步，就是1)利用人类基因的强大属性 斑马鱼系统识别驱动NC EMT和细胞迁移的新机制，以及2)确定是否抑制 儿童脑瘤模型中的一个或多个EMT效应器可防止肿瘤侵袭和/或扩散。 中心假设是细胞黏附、细胞骨架和/或信号分子的一个子集是必不可少的。 用于执行NC EMT，这些分子是抑制EMT诱导的大脑的有希望的靶点 肿瘤侵袭。在已公布和初步数据的指导下，这一假设将通过以下三个方面进行验证 具体目标我们将：1)确定高度保守的Foxd3转录因子是否直接控制 Snail基因在EMT中的表达，2)确定依赖Foxd3/Snail的EMT的主要效应因子 NC的发展和3)确定脑瘤体内侵袭是否需要一个或多个NC效应。 这项提议是创新的，因为它使用了新的遗传和成像技术来动态测量 并控制发育中的EMT计划在整个动物脑瘤侵袭过程中的影响 首次采用单细胞分辨率，能够快速识别大脑的新靶点和治疗方法 癌症。拟议研究的成功完成将产生重大影响，因为它是 期望垂直推进和扩大我们对如何操作发展性EMT的理解 在许多疾病背景下的方案，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.