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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：
10442375
负责人：
Min Yu
金额：
$ 36.99万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442375
关键词：
Alanine Binding Biological Assay Blood Blood - brain barrier anatomy Blood Circulation Brain Breast Cancer Cell Breast Cancer Patient CD100 antigen CRISPR/Cas technology Cathepsins Cell Polarity Cells Co-Immunoprecipitations Complex Complication Cytoplasm Cytoplasmic Tail Data Development Epithelial In Vitro Incidence Interruption Knock-out Knockout Mice Knowledge Ligands Ligation Link Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic malignant neoplasm to brain 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 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.

概括脑转移导致许多癌症类型（两种最常见的癌症）的显着发病率和死亡率是肺癌和乳腺癌。这种毁灭性的并发症是由循环系统中的一个罕见的子集引发的肿瘤细胞 (CTC) 流入血流。 CTC 穿过血脑屏障 (BBB) 的过程是启动脑转移的第一个关键步骤。因此，了解 CTC 如何破坏 BBB 至关重要发展意味着预测、预防或治疗脑转移。我们最近使用体外研究扩展了从乳腺癌患者中分离出的 CTC 鉴定出跨膜表面受体 SEMA4D，可促进通过与脑内皮上的配体 PLXNB1 结合，使 CTC 穿过血脑屏障，从而实现脑转移细胞（BEC）。我们的初步数据现在表明，SEMA4D 刺激会导致肿瘤中的 YAP/TAZ 信号传导细胞，众所周知促进细胞运动和迁移的途径，最近与发育有关脑转移。因此，我们假设通过 SEMA4D 发挥“反向信号”的作用细胞质尾部激活 YAP 信号传导，与 BEC 上的 SEMA4D-PLXNB1 协同作用违反 BBB。我们将利用我们独特的患者来源 CTC 资源以及体外和体内 BBB 轮回试验来检验我们的假设。该提案的总体目标是剖析详细的将 SEMA4D 与 YAP 信号传导联系起来的机制，以及 YAP 在 SEMA4D 介导的 BBB 迁移中的作用。描述 SEMA4D 和 YAP 信号传导的组合效应将使我们能够设计潜在的治疗方法预防 SEMA4D 介导的脑转移的方法。这些知识还将提供一种机制识别其他 BBB 迁移启动子的基础，这些启动子可以通过受体束缚来发挥类似的作用 BEC 和随后激活 YAP，这可能对识别预测产生更广泛的影响脑转移的生物标志物。