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The role of endothelial cells in the formation of early metastatic niches in the lung

内皮细胞在肺早期转移灶形成中的作用

基本信息

批准号：
10241023
负责人：
Sandra Ryeom
金额：
$ 1.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241023
关键词：
Angiogenesis Inhibitors Anoikis Antibodies Apoptosis Area Biological Assay Biopsy Blood Circulation CD44 gene Calcineurin Cancer Etiology Cancer Patient Cells Cessation of life Coculture Techniques Collagen Cytosol Data Disease Distant Down-Regulation Endothelial Cells Endothelium Environment Epithelial Epithelial Cells Experimental Models Exposure to Extracellular Matrix Extracellular Matrix Proteins Extravasation Fibronectins Generations Genes Glycoproteins Homeostasis Human In Vitro Investigation Knockout Mice Lesion Ligation Liver Location Lung Lung Neoplasms MMP3 gene Mediating Mediator of activation protein Mesenchymal Metalloproteases Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Methylation Modeling Mus Neoplasm Circulating Cells Neoplasm Metastasis Normal tissue morphology Organ Organoids Pilot Projects Play Prevention Primary Neoplasm Process Production Protein Isoforms Publishing Regulation Role Signal Transduction Site Soil Stress Stromal Cells Structure of parenchyma of lung TEK gene Tail Tamoxifen Thrombospondin 1 Time Tissue-Specific Gene Expression Translating Tumor-Derived Up-Regulation Veins Vimentin alveolar epithelium bisulfite sequencing cancer cell circulating cancer cell gastric cancer cell in vivo inhibitor/antagonist insight lung colonization mRNA Expression mRNA Stability malignant stomach neoplasm mortality mouse model neoplastic cell prevent programs promoter protein expression receptor therapeutic target transcription factor

项目摘要

SUMMARY Metastatic disease is a multistep cascade and is the primary cause of cancer-related mortalities. Many studies are investigating how tumor cells acquire the ability to metastasize to distant organs and escape from their primary location. However much less is known about the mechanisms underlying the colonization of normal organs by disseminated and circulating tumor cells, arguably the rate limiting step in metastatic progression. The lung is one of the most common sites of metastases therefore in this proposal, we will investigate the role of endothelial cells (ECs) in the normal lung during extravasation of circulating cancer cells out of the vessel lumen and colonization into the normal lung to establish lung metastases. Disseminated tumor cells undergo significant stress in the circulation such that during extravasation into the normal lung, they require a protective niche composed of extracellular matrix to provide physical anchorage to prevent anoikis and apoptosis. This protective niche allows disseminated tumor cells the opportunity to recover, survive and expand in the lung eventually becoming macrometastatic lesions. We are investigating the processes that activate lung ECs converting normal lung tissue into hospitable “soil” or an early metastatic niche (EMN) to facilitate colonization by circulating tumor cells. Our published studies and preliminary data suggest that lung ECs are activated prior to the arrival of tumor cells in mouse models of lung metastases. Our data also indicate that the matricellular glycoprotein, thrombospondin-1 (TSP1) plays an important role in regulating EC homeostasis during metastatic progression. Tumor cells that specifically metastasize to the lung and tumor conditioned media downregulates TSP1 in lung ECs promoting EC activation. Our pilot studies identified increased expression of matrix metalloproteases (MMPs) 3 in TSP1low ECs. Our preliminary data suggest that MMP3 promotes endothelial-to-mesenchymal through interactions with CD44 ultimately leading to increased extracellular matrix production and remodeling contributing to EMN generation in the lung. Our overarching hypothesis is that primary tumors that metastasize to the lung activate lung ECs by TSP1 downregulation leading to EndoMT and increased extracellular matrix production in the EMN supporting lung colonization. We propose that TSP1 is a critical regulator of EC homeostasis and its loss promotes EC activation and ultimately leads to extracellular matrix production and remodeling via an MMP3-CD44 axis. Understanding the contribution of ECs in the normal lung towards metastatic progression will offer new insight into the mechanisms underlying the earliest stages of lung metastases and may offer therapeutic targets for the prevention of metastatic disease.

总结