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

• 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
• 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

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.

项目摘要/摘要 转移是从原发性肿瘤传播到远处器官的转移 〜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出色，但经历了脑转移率升高。这 细胞因子IL4和IL13被多种人类实体瘤过表达。两者都是 与侵入性和转移性表型有关； IL13在 原发性脑肿瘤。这些细胞因子通过I型（仅IL4）和II型（IL4/IL13）IL4信号 受体（IL4R）。我们的实验室在发表的工作中表明，IL4R信号的遗传丧失 在肿瘤细胞中，小鼠模型中的肺和肝转移减弱。此外，我们最近 确定了II型IL4R信号传导在调节糖基化中的作用（添加糖 肿瘤细胞中的表位于蛋白质和脂质上）。 TCGA分析表明HER2+ 乳腺癌的II型IL4R水平升高，提出了II型IL4R的问题 信号传导对于该疾病亚型的生物学尤为重要。我们假设 II型IL4R信号传导至少部分地影响了HER2+乳腺癌脑转移 调节糖基化。 AIM 1解决转移的进展及其可能 使用HER2+乳腺癌的小鼠模型，对II型IL4R的依赖性，新型IL4封锁 代理商和一种称为Clarity的尖端技术，具有高分辨率， 全器图像。 AIM 2探测IL4R信号对早期转移行为的影响， 包括跨血脑屏障，肿瘤生长动力学和能力的移民 使用各种体外和外体技术，血管共选择和细胞 - 细胞粘附。目的 3解决了IL4/IL13刺激在HER2+乳腺癌中调节糖基化的能力 细胞和这些变化与早期转移行为的相关性。先前确定的 将验证与胶质母细胞瘤有关的辅助转移酶，包括辅助酶。 此外，我们建议使用QRT-PCR阵列和凝集素识别和验证新目标 探针。该项目将对HER2+乳腺癌大脑的机制产生新的见解 转移。由于IL4-和IL13靶向疗法已经处于各种迹象的试验中，因此 该提案的结果可能表明一种可行的临床方法来控制脑转移。