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

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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.