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

II 型 IL4R 信号传导对乳腺癌脑转移的影响

基本信息

批准号：
10454820
负责人：
Wendy Elizabeth Bindeman
金额：
$ 3.18万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454820
关键词：
Address Adhesions Affect Agar Anatomy Asthma Attenuated Behavior Biological Assay Biology Blood Blood - brain barrier anatomy Blood Circulation Blood Vessels Brain Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast cancer metastasis Cancer Biology Cell Survival Cell surface Cell-Cell Adhesion Cells Cephalic Cessation of life Clinical Consequentialism Cytokine Signaling Data Dependence Disease Distant ERBB2 gene Epithelial Cells Epitopes Frequencies Genetic Glioblastoma Growth Human Hypersensitivity IL4 gene Image Immune In Vitro Inflammatory Response Injections Interleukin 4 Receptor Interleukin-13 Kinetics Label Laboratories Lectin Lipids Liver Lung Malignant Neoplasms Mediator of activation protein Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Metastatic breast cancer Metastatic malignant neoplasm to brain Micrometastasis Modeling Morbidity - disease rate Mus Neoplasm Circulating Cells Neoplasm Metastasis Organ Palliative Care Pathway interactions Patients Pharmacology Phase Phenotype Play Post-Translational Protein Processing Primary Brain Neoplasms Primary Neoplasm Process Proteins Publishing Quantitative Reverse Transcriptase PCR Receptor Activation Receptor Signaling Resolution Role SLC2A1 gene Sialyltransferases Signal Transduction Slice Solid Neoplasm Source Techniques The Cancer Genome Atlas Therapeutic Tumor Biology Tumor Burden Work advanced disease base cell type clinically significant cytokine disorder subtype efficacy evaluation experience genetic manipulation glycosylation improved in vitro Model inhibitor innovation insight interest knock-down malignant breast neoplasm mind control mouse model neoplastic cell new therapeutic target novel overexpression response sugar targeted treatment tumor tumor growth tumor progression

项目摘要

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.

项目概要/摘要转移，即癌症从原发肿瘤向远处器官的传播，是造成约 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，但脑转移率仍升高。这细胞因子 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相关； IL13 在以下方面也很重要：原发性脑肿瘤。这些细胞因子通过 I 型（仅限 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 信号传导的遗传缺失在小鼠模型中，肿瘤细胞中的抗肿瘤药物可以减弱肺和肝转移。另外，我们最近确定了 II 型 IL4R 信号在调节糖基化（添加糖）中的作用肿瘤细胞中蛋白质和脂质上的表位。 TCGA 分析表明 HER2+ 乳腺癌的 II 型 IL4R 水平升高，提出了 II 型 IL4R 是否信号传导对于这种疾病亚型的生物学尤其重要。我们假设 II型IL4R信号传导至少部分通过影响HER2+乳腺癌脑转移糖基化的调节。目标 1 解决转移进展及其可能性使用 HER2+ 乳腺癌小鼠模型对 II 型 IL4R 的依赖性，新型 IL4 阻断代理，以及一种名为 CLARITY 的尖端技术，它能够高分辨率、全器官图像。目标 2 探讨 IL4R 信号传导对早期转移行为的影响，包括跨血脑屏障的迁移、肿瘤生长动力学和能力使用各种体外和离体技术进行血管选择和细胞间粘附。目的 3 阐述了 IL4/IL13 刺激调节 HER2+ 乳腺癌糖基化的能力细胞以及这些变化与早期转移行为的相关性。先前确定的候选者，包括与胶质母细胞瘤有关的唾液酸转移酶，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靶点探针。该项目将对 HER2+ 乳腺癌脑机制产生新的见解转移。由于 IL4 和 IL13 靶向疗法已经在针对各种适应症的试验中，该提案的结果可能为控制脑转移提供可行的临床方法。