Tumor-endothelium interactions are critical for tumor survival and metastasis. Melanomas can rapidly metastasize early in tumor progression, but the dependence of this aggressive behavior on tumor-stromal interaction is poorly understood. To probe the mechanisms involved, we developed a heterotypic coculture methodology, allowing simultaneous tracking of genomic and phenotypic changes in interacting tumor and endothelial cells in vitro. We found a dramatic rearrangement of endothelial cell networks into patterns reminiscent of vascular beds, even on plastic and glass. Multiple genes were upregulated in the process, many coding for cell surface and secreted proteins, including Neuropilin-2 (NRP2). A critical role of NRP2 in coordinated cell patterning and growth was confirmed using the coculture system. We conclude that NRP2 represents an important mediator of melanoma-endothelial interactions. Furthermore, the described methodology represents a powerful yet simple system to elucidate heterotypic intercellular interactions mediating diverse physiological and pathological processes.