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Mechanisms of SEMA4D mediated breast cancer to brain metastasis

SEMA4D介导乳腺癌脑转移的机制

基本信息

批准号：
10889447
负责人：
Min Yu
金额：
$ 34.49万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10889447
关键词：
Alanine Binding Biological Assay Blood Blood - brain barrier anatomy Brain Breast Cancer Cell Breast Cancer Patient CD100 antigen CRISPR/Cas technology Cathepsins Cell Polarity Cell Separation Cells Cephalic Circulation Co-Immunoprecipitations Complex Complication Cytoplasm Cytoplasmic Tail Data Development Epithelium In Vitro Incidence Interruption Knock-out Knockout Mice Knowledge Ligands Ligation Link Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Metastatic malignant neoplasm to brain Migration Assay Modeling Molecular Morbidity - disease rate Mutate Nature Neoplasm Circulating Cells PDZ protein Pathway interactions Patients Peptides Phosphorylation Proteins Publishing Regulation Research Resources Role Sampling Serine Signal Transduction Stream Surface Systemic Therapy Testing Therapeutic Tight Junctions blood-brain barrier crossing blood-brain tumor barrier brain endothelial cell cancer type cell motility connective tissue growth factor design in vivo malignant breast neoplasm migration mortality mouse model mutant neoplastic cell overexpression patient prognosis predictive marker prevent protein complex receptor small hairpin RNA synergism targeted treatment tumor

项目摘要

Summary Brain metastasis accounts for significant morbidity and mortality of many cancer types, the two most common being lung and breast cancers. This devastating complication is initiated by a rare subset of the circulating tumor cells (CTCs) shed into the blood stream. The crossing of the blood-brain barrier (BBB) by CTCs is the first critical step that initiates brain metastasis. Thus, understanding how CTCs can breach the BBB is critical for developing means to predict, prevent, or treat brain metastasis. Our recent study using ex vivo expanded CTCs isolated from breast cancer patients identified a transmembrane surface receptor, SEMA4D, promotes brain metastasis by enabling CTCs to cross the BBB via binding to its ligand PLXNB1 on the brain endothelial cells (BECs). Our preliminary data now show that SEMA4D stimulation leads to YAP/TAZ signaling in tumor cells, a pathway well known to promote cell motility and migration, and recently implicated in the development of brain metastasis. Therefore, we hypothesize a role for “reverse signaling” through the SEMA4D cytoplasmic tails to activate YAP signaling for synergizing with SEMA4D-PLXNB1 tethering to the BECs to breach the BBB. We will utilize our unique resources of patient-derived CTCs, and in vitro and in vivo BBB transmigration assays to test our hypothesis. The overall objective of this proposal is to dissect the detailed mechanisms linking SEMA4D to YAP signaling, and the role for YAP in SEMA4D-mediated BBB transmigration. Delineating the combinatory effect of SEMA4D and YAP signaling will allow us to design potential therapeutic approaches to prevent SEMA4D-mediated brain metastasis. Such knowledge will also provide a mechanistic basis for identifying additional BBB transmigration initiators that could act similarly through receptor tethering to BECs and subsequent activation of YAP, which could have a broader impact on identifying predictive biomarkers for brain metastasis.

总结脑转移占许多癌症类型的显著发病率和死亡率，这两种最常见的肺癌和乳腺癌。这种毁灭性的并发症是由一种罕见的循环中的亚群引起的。肿瘤细胞（CTC）脱落进入血流。CTC穿过血脑屏障（BBB）是肿瘤细胞进入血脑屏障的主要途径。因此，了解CTC如何突破血脑屏障是至关重要的用于开发预测、预防或治疗脑转移的方法。我们最近的研究使用离体扩大了从乳腺癌患者中分离的CTC鉴定出一种跨膜表面受体SEMA 4D，通过使CTC能够通过与脑内皮细胞上的配体PLXNB 1结合而穿过BBB，我们的初步数据现在显示，SEMA 4D刺激导致肿瘤细胞中的雅普/TAZ信号传导。细胞，一种众所周知的促进细胞运动和迁移的途径，最近与发育有关。因此，我们假设通过SEMA 4D的“反向信号”的作用，细胞质尾区以激活雅普信号传导，从而与SEMA 4D-PLXNB 1结合至BEC协同作用，我们将利用我们独特的患者来源的CTC资源，以及体外和体内BBB，轮回实验来检验我们的假设。这个提议的总体目标是剖析 SEMA 4 D与雅普信号传导的联系机制，以及雅普在SEMA 4 D-β介导的BBB迁移中的作用。阐明SEMA 4D和雅普信号传导的联合作用将使我们能够设计潜在的治疗方案。预防SEMA 4D-β介导的脑转移的方法。这些知识也将提供一个机制，确定其他BBB迁移引发剂的基础，这些引发剂可以通过受体拴系类似地起作用， BEC和随后的雅普激活，这可能对识别预测性脑转移的生物标志物。