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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：
10188472
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/10188472
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 Prognosis 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 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