Among a plethora of functions, extracellular vesicles released by primary tumors spread in the organism and reach distant organs where they can induce the formation of a premetastatic niche. This constitutes a favorable microenvironment for circulating tumor cells which facilitates their seeding and colonization. Researchers from INSERM describe the journey of extracellular vesicles (EVs) from the primary tumor to the future metastatic organ, with a focus on the mechanisms used by EVs to target organs with a specific tropism (i.e., organotropism). They then highlight important tumor EV cargos in the context of premetastatic niche formation and summarize their known effects on extracellular matrix remodeling, angiogenesis, vessel permeabilization, resident cell activation, recruitment of foreign cells, and ultimately the formation of a pro-inflammatory and immuno-tolerant microenvironment. Finally, the researchers discuss current experimental limitations and remaining opened questions in light of metastatic diagnosis and potential therapies targeting PMN formation
Tumor extracellular vesicles prime premetastatic niches
The journey of EVs from the primary tumor to the future metastatic organ is a multistep process initiated with the secretion of tumor‐derived EVs and other tumor‐derived soluble factors (TDSF) from the primary tumor. 1. Upon secretion, tumor‐derived EVs leave the primary tumor and travel through the blood and lymphatic circulation, where they interact with blood components like neutrophils, endothelial cells, platelets, low‐density lipoproteins (LDL), and other immune cells. These interactions affect blood homeostasis, enhance the uptake of tumor EVs by distinct recipient cells, and could induce endothelial permeabilization, thereby promoting the formation of premetastatic niche (PMN). 2. Tumor EVs are further taken up by patrolling monocytes and endothelial cells and some of the tumor EVs pass through the impermeable endothelial cells within the tissue by transcytosis. Uptake of tumor EVs by these recipient cells can directly impact the PMN formation. Inset shows a magnified tumor EV, that are encapsulated by a lipid bilayer, containing various biomolecules such as DNA, RNA, proteins as well glycans, specialized receptors at their surface (CD47, CD9, and CD63), and several adhesion proteins such as integrins and MCAM. 3. Key features of the PMN. Highlighted are the key features of the PMN and their associated tumor EV cargos that actively contribute to efficient PMN formation. Upon internalization by distinct recipient cells, tumor EVs deliver their cargo, induce phenotypic changes in them, thereby promoting ECM remodeling, reprogramming cell metabolism, inducing immunomodulation, angiogenesis and vascular permeability, lymphangiogenesis, and also triggering pro‐inflammatory molecules. All these salient features eventually promote PMN formation. 4. Following the PMN formation, circulating tumor cells (CTCs) eventually reach the PMN and colonize in the new tissue, leading to metastasis. Highlighted in the far left, is the human women model demonstrating organotrophic metastasis, where primary breast tumor‐secreted EVs prime PMN at distant organs such as lungs, brain, liver, and bone.