Updated project metadata. Metastaticsis disease remains, by far, the leading cause of all cancer-related deaths, despite being a process highly inefficient. The metastatic process is highly inefficient as the initial dissemination of cancer cells from many primary tumors involves intravasation to lymphatics nodes or blood vessels, a process poorly understood. To investigate generalthe molecular mechanisms involved in this step we analyzed the expression of the epigenetic regulators small non-coding RNAs (sncRNAs) in cutaneous squamous cell carcinoma (cSCC), a highly prevalent malignant tumor that mainly spreads to lymph nodes. Here we report the reduced expression of small nucleolar RNAs (snoRNAs) in primary cSCCs that metastasized when compared to non-metastasizing cSCCs, and the progressive loss of DKC1 (the protein that stabilizes the snoRNAs) along the metastasis of the carcinomas. DWe demonstrate that depletion of DKC1 in cSCC cells resulted in a switch totriggers lipid metabolism and the acquisition of metastatic traits. Treatment of DKC1-depleted cells with simvastatin, an inhibitor of the mevalonate pathway, blocked the expression of proteins involved in the epithelial to mesenchymal transition (EMT), suggesting that the rewiring of the lipid metabolism is required to acquire the invasion abilities. Furthermore, the expression of the enzyme HMGCS1 is associated with pathologic features of high metastatic risk in cSCC patients, underpinning the relevance of the mevalonate metabolism in the lymphatic dissemination step.