Cancer-associated fibroblast-derived extracellular vesicles regulate lipophagy through PLIN2 to modulate dormancy in salivary gland adenoid cystic carcinoma cells

Abstract Tumor recurrence and metastasis are largely attributed to dormant tumor cells receiving reactivation signals, particularly those originating from the tumor microenvironment. However, the detailed mechanisms of dormant tumor cell reactivation in salivary gland adenoid cystic carcinoma (SACC) remain largely unknown. Here our data revealed that autophagy is activated in dormant SACC cells but becomes downregulated once these cells are reactivated, and that cancer-associated fibroblast (CAF)-mediated autophagy promotes dormant SACC cells to resume proliferation and escape dormancy. Mechanistically, PLIN2 encapsulated in CAFs-derived extracellular vesicles promoted the initial stage of autophagy through the endoplasmic reticulum stress signaling pathway, and directly bound to p62 to promote lipid droplet degradation through the lipophagy pathway, which provided energy for the reactivation of dormant SACC cells. Moreover, we confirmed that PLIN2 expression was remarkably correlated with poor survival in patients with SACC. Finally, we verified that the combination of tozasertib and PLIN2 was stable through molecular docking and molecular dynamics simulation, indicating that tozasertib has the potential to serve as a targeted PLIN2 drug for CAFs in SACC. Our findings suggest that targeting PLIN2 and autophagy inhibition as part of primary SACC treatment may effectively eliminate dormant tumor cells and prevent SACC recurrence.