The study investigates the early colonization process of metastatic tumor cells (mTCs) in the lung and the role of the endothelium in instructing metastatic latency. Using a combinatorial mTC enrichment approach, the researchers provide a transcriptional blueprint of the initial colonization process. They find that mTCs either proliferate intravascularly or extravasate, leading to metastatic latency. Endothelial-derived Wnt factors play a crucial role in this decision, driving mTCs towards the extravasation–latency route. Surprisingly, mTC responsiveness to niche-derived Wnt is established at the epigenetic level, with hypomethylated mTCs exhibiting high Wnt activity and metastatic latency, while methylated mTCs show low activity and proliferate intravascularly. The study identifies the methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche. The findings highlight the importance of the endothelium as a crucial interface in the dissemination process and suggest that the initial arrival of mTCs at the metastatic site is a critical moment for determining their fate.The study investigates the early colonization process of metastatic tumor cells (mTCs) in the lung and the role of the endothelium in instructing metastatic latency. Using a combinatorial mTC enrichment approach, the researchers provide a transcriptional blueprint of the initial colonization process. They find that mTCs either proliferate intravascularly or extravasate, leading to metastatic latency. Endothelial-derived Wnt factors play a crucial role in this decision, driving mTCs towards the extravasation–latency route. Surprisingly, mTC responsiveness to niche-derived Wnt is established at the epigenetic level, with hypomethylated mTCs exhibiting high Wnt activity and metastatic latency, while methylated mTCs show low activity and proliferate intravascularly. The study identifies the methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche. The findings highlight the importance of the endothelium as a crucial interface in the dissemination process and suggest that the initial arrival of mTCs at the metastatic site is a critical moment for determining their fate.