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

项目总结/摘要 转移，即癌症从原发肿瘤向远处器官的扩散， 约90%的癌症死亡，是发病率的重要来源。HER2+乳腺癌患者 尽管原发性肿瘤控制良好，但脑转移率升高。的 细胞因子IL 4和IL 13在多种人实体瘤中过表达。两者都是 与侵袭性和转移性表型相关; IL 13还在 原发性脑肿瘤这些细胞因子通过I型（仅IL 4）和II型（IL 4/IL 13）IL 4 受体（IL 4R）。我们的实验室在已发表的工作中表明，IL4R信号传导的遗传缺失 在小鼠模型中，在肿瘤细胞中减少肺和肝转移。此外，我们最近 鉴定了II型IL4R信号在调节糖基化（糖的添加）中的作用 蛋白质和脂质上的表位）。TCGA分析表明，HER2 + 乳腺癌具有升高的II型IL4R水平，这提出了II型IL4R是否 信号传导对于这种疾病亚型的生物学可能特别重要。我们假设 II型IL4R信号传导至少部分通过以下途径影响HER2+乳腺癌脑转移： 糖基化的调节。目的1解决转移性进展及其可能的 使用HER2+乳腺癌小鼠模型的II型IL4R依赖性，新型IL4阻断 代理商，和一个尖端的技术，称为并行性，这是能够高分辨率， 全器官图像目的2探讨IL 4R信号通路对肿瘤早期转移行为的影响， 包括穿过血脑屏障的迁移、肿瘤生长动力学和 血管共选择和细胞-细胞粘附，使用多种体外和离体技术。目的 3阐述了IL 4/IL 13刺激调节HER2+乳腺癌中糖基化的能力 这些变化与早期转移行为的相关性。先前识别 包括胶质母细胞瘤中涉及的唾液酸转移酶在内的候选物将被验证。 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标。 probes.该项目将对HER2+乳腺癌脑机制产生新的见解 转移由于IL 4和IL 13靶向疗法已经在各种适应症的试验中， 该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.