Non-neoplastic cell types dictate gliomagenesis and

描述（由申请人提供）：来自我们各个实验室的数据支持这样一种观点，即脑癌（胶质瘤）是由几种非肿瘤细胞类型组成的复杂动态生态系统，这些细胞类型对胶质瘤的形成和维持至关重要。具体来说，我们已经证明肿瘤微环境中的一种非肿瘤细胞类型（小胶质细胞）是胶质瘤细胞生长和侵袭的关键决定因素。为了更完整地定义肿瘤微环境调控胶质瘤行为的分子机制，我们组建了一个高度互动的研究团队，包括一个早期研究肿瘤微环境的研究者（Dolores Hambardzumyan），一个小胶质细胞-胶质瘤相互作用的资深科学家专家（Helmut Kettenmann），以及两位知名的内科科学家（Eric Holland和David Gutmann），他们的实验室采用基因工程小鼠模型（GEMMs）来评估胶质瘤中非肿瘤细胞和肿瘤细胞之间的动态相互作用。基于我们每个实验室的实验结果，我们假设肿瘤胶质细胞（胶质瘤细胞）招募并改变原有脑小胶质细胞的功能，以产生专门的肿瘤相关小胶质细胞，这些小胶质细胞精心制作的分子既可以产生允许的基质（“基质生成”）（Aim 1），也可以激活星形胶质细胞（Aim 2）。这些“反应性”星形胶质细胞支持血管周围生态位（胶质瘤原）的产生和维持（Aim 3），它为癌症干细胞提供了适当的微环境-胶质瘤细胞的治疗抵抗群体（Aim 4）。总的来说,这

DESCRIPTION (provided by applicant): Converging data from our individual laboratories support the notion that brain cancers (gliomas) are complex and dynamic ecosystems composed of several non-neoplastic cell types critical for glioma formation and maintenance. Specifically, we have shown that one of these non-neoplastic cell types (microglia) in the tumor microenvironment is a critical determinant of glioma cell growth and invasion. To more completely define the molecular mechanisms underlying tumor microenvironment regulation of glioma behavior, we have assembled a highly interactive team of researchers, including one early stage investigator focused on the tumor microenvironment (Dolores Hambardzumyan), one senior scientist expert in microglia-glioma interactions (Helmut Kettenmann), and two established physician-scientists (Eric Holland and David Gutmann) whose laboratories employ genetically engineered mouse models (GEMMs) to evaluate the dynamic interactions between non-neoplastic and neoplastic cells in glioma. Based on experimental findings from each of our individual laboratories, we hypothesize neoplastic glia (glioma cells) recruit and alter the function of resident brain microglia to create specialized tumor-associated microglia, that elaborate molecules that both create a permissive stroma ("stromagenesis") (Aim 1) and activate astrocytes (Aim 2). These "reactive" astrocytes support the creation and maintenance of the perivascular niche (gliomagens) (Aim 3), which provides the proper microenvironment for cancer stem cells - the treatment-resistant population of glioma cells (Aim 4). Collectively, this cross-disciplinary initiative capitalizes on converging lines of evidence that conceptualize gliomas as dynamic ecosystems composed of neoplastic and non-neoplastic cells and leverages expertise in mouse modeling, glioma biology, tumor microenvironment, microglia function, and translational medicine to identify new therapeutic targets for treating these deadly brain cancers.