In conclusion, we demonstrate that loss of TRPML1 function leads to disturbed trafficking of important regulators of migration, that is, E-cadherin, β1-integrin, and cytoskeleton organization resulting in reduced migration and adhesion of cancer cells in vitro and reduced dissemination in vivo. Furthermore, the loss of E-cadherin levels at membrane site lead to a p38-mediated activation (RIL-175) or inhibition (MDA-MB-231) of NF-κB and therefore form a transcriptional feedback for E-cadherin expression. Here, MCOLN1 is linked to cancer.