All forms of cancer begin with genetic alterations in otherwise healthy stem cells. Yet, these alone are insufficient to predict when a person might develop the disease or how severe it might be. This raises the possibility that nongenetic events within the tumor ecosystem play a role in unleashing tumorigenesis. The goal of this proposal is to determine how the lymphatic system shapes the stem cell oncogenic landscape throughout cancer initiation and progression. We found that tumor-initiating stem cells rely on their connections with lymphatic vessels, typically considered as the waste drains of the body. Using a model of skin cancer, we are proposing a new tool to track cancer cells in their natural habitat to find how lymphatic vessels shield cancer cells and aid their spread to other parts of the body. A successful outcome of our studies holds promise for the development of therapeutics that block early cancer progression and pave the way to combat advanced metastatic disease.