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：
10037481
负责人：
Min Yu
金额：
$ 37.74万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10037481
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 Epithelium 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 outcome forecast overexpression 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.

概括脑转移占了严重的病态和许多癌症类型，这两种最常见肺部和乳腺癌。肿瘤细胞（CTC）脱落到血液中。因此，启动大脑转移的第一步。用于预测，预防或信任大脑转移的手段。从乳腺癌患者中分离出的CTC鉴定出跨膜表面受体SEMA4D促进通过使CTC通过与其在脑内皮内细胞上的配体PLXNB1结合，通过使CTC越过BBB来转移脑转移单元格（BEC）。细胞是一种众所周知的途径，可促进细胞运动和迁移，最近在发育中含义因此，大脑转移。细胞质尾巴激活YAP信号传导，以与SEMA4D-PLXNB1协同为BEC将违反BBB。迁移测定以检验我们的假设。将SEMA4D与YAP信号联系起来的机制，以及YAP在SEMA4D介导的BBB传输中的作用。描述SEMA4D和YAP信号的组合效应将使我们能够设计潜在的治疗性防止SEMA4D介导的脑转移的方法。识别其他BBB迁移启动者的基础，这些启动者可能会以类似的方式绑定到与 BEC和随后的YAP激活脑转移的生物标志物。