Basal EFNA3 Facilitates Luminal-Driving Mammary Epithelial Migration and Cancer Metastasis by Promoting OXPHOS

Collective migration is essential for tissue development, repair, and cancer metastasis. However, the mechanisms by which different cell types coordinate to facilitate cohesive movement remain poorly understood. Here, we report distinct migratory behaviors in luminal and basal cells during collective migration of the mammary epithelium. We show that luminal cells are leaders of directional migration. However, basal cells also play a central role in promoting collective migration by producing EFNA3, which targets luminal cells and enhances oxidative phosphorylation and energy production. This promotion of epithelial migration and branching morphogenesis is confirmed in vivo. Importantly, EFNA3 is a prognostic marker for breast cancer metastasis, with high expression correlating with increased metastasis. Conversely, inhibition of EFNA3 significantly slows metastasis. These findings reveal a novel mechanism of epithelial migration that is critical for organogenesis and identify EFNA3 as a potential therapeutic target for cancer metastasis.