Non-neoplastic cell types dictate gliomagenesis and

描述(申请人提供)：来自我们各个实验室的汇聚数据支持脑癌(胶质瘤)是由几种对胶质瘤的形成和维持至关重要的非肿瘤细胞类型组成的复杂而动态的生态系统的概念。具体地说，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。为了更完整地确定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，其中包括一名专注于肿瘤微环境的早期研究员(Dolores Hambardzumyan)、一名研究小胶质细胞与胶质瘤相互作用的资深科学家(Helmut Kettenmann)和两位资深内科医生兼科学家(Eric Holland和David Gutmann)，他们的实验室采用基因工程小鼠模型(GEMM)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。根据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)招募并改变常驻脑小胶质细胞的功能，以创造专门的肿瘤相关小胶质细胞，这种特殊的分子既能创造允许的间质(“基质形成”)(目标1)，又能激活星形胶质细胞(目标2)。这些“反应性”星形胶质细胞支持血管周围壁龛(胶质瘤细胞)的产生和维持(目标3)，为肿瘤干细胞提供适当的微环境--胶质瘤细胞的抗药性群体(目标4)。总而言之，这 跨学科的倡议利用了将胶质瘤概念化为由肿瘤和非肿瘤细胞组成的动态生态系统的各种证据，并利用小鼠建模、胶质瘤生物学、肿瘤微环境、小胶质细胞功能和转化医学方面的专业知识来确定治疗这些致命脑癌的新治疗靶点。

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.