Targeting extracellular signaling-regulated kinase 5 (ERK5) in brain tumors and their microenvironment

背景：高级别胶质瘤是儿童癌症相关死亡的主要原因之一， 弥漫性内在脑桥神经胶质瘤（DIPG）是一种高度致命的亚型。 DIPG 通常表现出突变 组蛋白 H3，称为 H3K27M，可导致神经胶质瘤发生。然而，细胞信号传导事件 促进 DIPG 生长尚不完全清楚。我们最近发现并证明 DIPG 具有依赖性 细胞外信号调节激酶 5 (ERK5) 对增殖和存活的影响。然而，几个关键 DIPG 中 ERK5 功能的知识差距仍然存在。我们将使用创新的同源 DIPG 模型 与成熟的 DIPG 模型相结合来解决本提案中的几个问题。具体来说， 我们假设 ERK5 通过神经胶质瘤的内在作用和前神经胶质瘤活性来促进生长 选择神经胶质瘤相关的小胶质细胞和巨噬细胞（GAM）。意义：支持我们的初步数据 为了检验我们的假设，我们将研究 ERK5 在三个目标中的作用。目标 1：揭示 ERK5 在 GAM 以及 DIPG 细胞旁分泌信号传导的重要性将提供潜在的宝贵知识 适用于新治疗方法的开发。目标 2：建立新范式 了解针对多个 ERK 通路的动态特征。目标 3：ERK5 包含 反式激活结构域和激酶结构域与所有其他 ERK 不同。这里我们将描述其功能角色 这些领域及其对神经胶质瘤生长的贡献。影响。该项目利用了独特的体内和体内 研究高度侵袭性脑肿瘤的体外模型系统。我们的研究将揭示分子机制 以及 ERK5 在脑肿瘤中的翻译相关性，并广泛适用于其他类型的癌症和 神经科学。

Background: High-grade gliomas are among the leading cause of cancer-related death in children, with diffuse intrinsic pontine glioma (DIPG) being a highly lethal subtype. DIPG commonly exhibits a mutation in histone H3, referred to as H3K27M, which leads to gliomagenesis. However, the cell signaling events that promote DIPG growth are not fully understood. We have discovered and recently shown that DIPGs are reliant on extracellular signal-regulated kinase 5 (ERK5) for proliferation and survival. However, several critical knowledge gaps of ERK5 function in DIPG remain. We will use an innovative syngeneic DIPG model in combination with well-established models of DIPG to address several questions in this proposal. Specifically, we hypothesize that ERK5 promotes growth through both glioma intrinsic effects and pro-glioma activities of select glioma associated microglia and macrophages (GAMs). Significance: To support our preliminary data and test our hypothesis we will study the role of ERK5 in three aims. Aim 1: Revealing functions of ERK5 in GAMs and the importance of paracrine signaling with DIPG cells will provide valuable knowledge potentially applicable to the development of new therapeutic modalities. Aim 2: Building a new paradigm by understanding the dynamic characteristics of targeting multiple ERK pathways. Aim 3: ERK5 contains both a transactivation domain and kinase domain unlike all other ERKs. Here we will delineate the functional role of these domains and their contribution to glioma growth. Impact. This project leverages unique in vivo and in vitro model systems to study a highly aggressive brain tumor. Our research will inform molecular mechanisms and translational relevance of ERK5 in brain tumors, and be broadly applicable to other types of cancer and neurosciences.