Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency. Cancer cells travel through the bloodstream to colonize distant sites, but the fate of metastasizing tumor cells (mTCs) is poorly understood. Using a new method, researchers identified the transcriptional blueprint of the early colonization process. After arresting at the metastatic site, mTCs either proliferate intravascularly or extravasate, establishing metastatic latency. Endothelial-derived Wnt factors drive this decision, instructing mTCs to follow the extravasation–latency route. mTC responsiveness to Wnt is established at the epigenetic level, which determines tumor cell behavior. Hypomethylation enables high Wnt activity leading to metastatic latency, while methylated mTCs proliferate intravascularly. The data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche. Metastatic latency and tumor cell dormancy are major challenges in cancer treatment. During metastasis, latent tumor cells (LTCs) reside near blood vessels and acquire a stem-like phenotype. However, metastasizing tumor cells show heterogeneity in genetic and molecular makeup, which can be attributed to some cells reaching a latent state while others outgrow to form macrometastases. This behavior is influenced by the metastatic niche, which can favor TC proliferation or be tumor suppressive. The induction of latency depends on cell-intrinsic properties and matching microenvironmental factors. Disseminated TCs, once committed to a dormant fate, require dramatic events to be awakened. Wnt and epithelial-to-mesenchyme transition (EMT) pathways drive extravasation and latency. Researchers developed an experimental model to assess TC and endothelial cell interactions in the metastatic niche. They used 4T1-GFP breast cancer cells and isolated lung-seeded TCs and total lung endothelial cells. Single-cell RNA sequencing was used to analyze TC-EC interactions during metastatic colonization. They found that LTCs persisted in the lung for at least 2 weeks, indicating a stable latent phenotype. Pseudotemporal ordering of events showed that proliferation preceded extravasation and latency induction. Lung endothelium displays a bimodal response following arrival of mTCs. Researchers classified ECs into known lung-specific subtypes and found that gCaps showed an immediate response pattern, while aCaps showed little transcriptional dynamics. Clustering analysis revealed the emergence of a gCap subpopulation that clustered with large-vessel ECs. DGEA showed upregulation of mostly metabolic and ribosomal genes, indicating enhanced biosynthesis and general activation. Angiokine gene expression was globally and temporally upregulated across all capillary ECs. Angiocrine Wnt ligands instruct metastatic latency. Researchers analyzed the consequences of the Wnt signature in LTCs. They treated 4Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency. Cancer cells travel through the bloodstream to colonize distant sites, but the fate of metastasizing tumor cells (mTCs) is poorly understood. Using a new method, researchers identified the transcriptional blueprint of the early colonization process. After arresting at the metastatic site, mTCs either proliferate intravascularly or extravasate, establishing metastatic latency. Endothelial-derived Wnt factors drive this decision, instructing mTCs to follow the extravasation–latency route. mTC responsiveness to Wnt is established at the epigenetic level, which determines tumor cell behavior. Hypomethylation enables high Wnt activity leading to metastatic latency, while methylated mTCs proliferate intravascularly. The data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche. Metastatic latency and tumor cell dormancy are major challenges in cancer treatment. During metastasis, latent tumor cells (LTCs) reside near blood vessels and acquire a stem-like phenotype. However, metastasizing tumor cells show heterogeneity in genetic and molecular makeup, which can be attributed to some cells reaching a latent state while others outgrow to form macrometastases. This behavior is influenced by the metastatic niche, which can favor TC proliferation or be tumor suppressive. The induction of latency depends on cell-intrinsic properties and matching microenvironmental factors. Disseminated TCs, once committed to a dormant fate, require dramatic events to be awakened. Wnt and epithelial-to-mesenchyme transition (EMT) pathways drive extravasation and latency. Researchers developed an experimental model to assess TC and endothelial cell interactions in the metastatic niche. They used 4T1-GFP breast cancer cells and isolated lung-seeded TCs and total lung endothelial cells. Single-cell RNA sequencing was used to analyze TC-EC interactions during metastatic colonization. They found that LTCs persisted in the lung for at least 2 weeks, indicating a stable latent phenotype. Pseudotemporal ordering of events showed that proliferation preceded extravasation and latency induction. Lung endothelium displays a bimodal response following arrival of mTCs. Researchers classified ECs into known lung-specific subtypes and found that gCaps showed an immediate response pattern, while aCaps showed little transcriptional dynamics. Clustering analysis revealed the emergence of a gCap subpopulation that clustered with large-vessel ECs. DGEA showed upregulation of mostly metabolic and ribosomal genes, indicating enhanced biosynthesis and general activation. Angiokine gene expression was globally and temporally upregulated across all capillary ECs. Angiocrine Wnt ligands instruct metastatic latency. Researchers analyzed the consequences of the Wnt signature in LTCs. They treated 4