Wipf_2026_Development__

While lipid droplets (LDs), organelles central to lipid and energy homeostasis, are implicated in cancer cell migration, their roles during collective cell migration remain unknown. We use Drosophila border cell (BC) migration as an in vivo model of invasive, collective migration to dissect the roles of LDs and the conserved LD lipase, Adipose Triglyceride Lipase (ATGL). LDs undergo dynamic changes and exhibit a polarized distribution during BC migration. Loss of ATGL increases LD volume, whereas BC ATGL overexpression depletes LDs. Loss, knockdown or overexpression of ATGL delays migration and impairs delamination. Additionally, loss of ATGL disrupts BC mitochondria functions, including membrane potential. Similarly, loss of the mitochondrial fatty acid importer, carnitine palmitoyltransferase 1 (CPT1), reduces mitochondrial membrane potential and severely blocks delamination. These results demonstrate that tight regulation of lipid mobilization from LDs, including for energy production, drives delamination and collective migration. These findings not only inform how cancer cells may exploit LDs to promote their invasive behaviors but also highlight the crucial role of LDs in migration during development, hinting at their broader significance in diverse migratory contexts.