The Impact of Type II IL4R Signaling on Breast Cancer Brain Metastasis

项目摘要/摘要 转移，即癌症从原发肿瘤扩散到远处器官，占 约90%的癌症死亡，是发病率的重要来源。HER2+乳腺癌患者 尽管原发肿瘤控制良好，但脑转移率仍较高。这个 细胞因子IL4和IL13在多种人类实体瘤中过度表达。两者都是 与侵袭性和转移性表型有关；IL13在 原发脑瘤。这些细胞因子通过I型(仅IL4)和II型(IL4/IL13)IL4发出信号 受体(IL4R)。我们的实验室在已发表的工作中表明，IL4R信号的遗传丢失 在一种小鼠模型中，肿瘤细胞可以减少肺和肝脏的转移。另外，我们最近 确定了II型IL4R信号在调节糖基化(糖的添加)中的作用 肿瘤细胞中的蛋白质和脂类)。TCGA分析表明，HER2+ 乳腺癌II型IL4R水平升高，引发了II型IL4R是否 信号可能对这种疾病亚型的生物学特别重要。我们假设 II型IL4R信号对HER2+乳腺癌脑转移的影响至少部分通过 糖基化的调节。目标1解决转移进展及其可能的问题 HER2+乳腺癌小鼠模型对II型IL4R的依赖性，新型IL4拮抗剂 以及一种名为Clarity的尖端技术，它能够实现高分辨率， 整个器官的图像。目的2探讨IL4R信号转导对肿瘤早期转移行为的影响。 包括跨血脑屏障的迁移，肿瘤生长动力学，以及 血管选择性和细胞-细胞黏附，使用各种体外和体外技术。目标 3阐述了IL4/IL13刺激对HER2+乳腺癌糖基化的调节能力 以及这些变化与早期转移行为的相关性。以前确定的 候选基因，包括与胶质母细胞瘤有关的唾液酸基转移酶，将得到验证。 此外，我们建议使用qRT-PCR阵列和凝集素来识别和验证新的靶点 探测器。该项目将对HER2+乳腺癌脑的机制产生新的见解 转移。由于IL4和IL13靶向治疗已经在各种适应症的试验中， 这一建议的结果可能为控制脑转移瘤提供一种可行的临床方法。

PROJECT SUMMARY/ABSTRACT Metastasis, the dissemination of cancer from the primary tumor to distant organs, accounts for ~90% of cancer deaths and is a significant source of morbidity. HER2+ breast cancer patients experience elevated rates of brain metastasis despite excellent primary tumor control. The cytokines IL4 and IL13 are overexpressed by a variety of human solid tumors. Both are associated with invasive and metastatic phenotypes; IL13 is additionally consequential in primary brain tumors. These cytokines signal through type I (IL4 only) and type II (IL4/IL13) IL4 receptors (IL4R). Our laboratory has shown in published work that genetic loss of IL4R signaling in tumor cells attenuates lung and liver metastasis in a mouse model. Additionally, we recently identified a role for type II IL4R signaling in modulating glycosylation (the addition of sugar epitopes onto proteins and lipids) in tumor cells. TCGA analysis demonstrates that HER2+ breast cancer has elevated levels of type II IL4R, raising the question of whether type II IL4R signaling may be particularly important for the biology of this disease subtype. We hypothesize that type II IL4R signaling influences HER2+ breast cancer brain metastasis at least in part via modulation of glycosylation. Aim 1 addresses metastatic progression and its possible dependency on type II IL4R using mouse models of HER2+ breast cancer, novel IL4 blockade agents, and a cutting-edge technique called CLARITY which is capable of high-resolution, whole-organ images. Aim 2 probes the influence of IL4R signaling on early metastatic behavior, including transmigration across the blood-brain barrier, tumor growth kinetics, and capacity for vascular co-option and cell-cell adhesion, using a variety of in vitro and ex vivo techniques. Aim 3 addresses the ability of IL4/IL13 stimulation to modulate glycosylation in HER2+ breast cancer cells and the relevance of those changes to early metastatic behavior. Previously identified candidates, including a sialyltransferase implicated in glioblastoma, will be validated. Additionally, we propose to identify and validate novel targets using qRT-PCR arrays and lectin probes. This project will yield novel insights into the mechanism of HER2+ breast cancer brain metastasis. As IL4- and IL13-targeted therapies are already in trials for various indications, the results of this proposal may suggest a feasible clinical approach for control of brain metastasis.