METTL3 regulates exocytosis independently of m ⁶ A

RNA modification pathways are often mis-regulated in various cancers, with N6-methyladenosine (m ⁶ A) having a pivotal role in cancer progression and metastasis. Methyltransferase-like 3 (METTL3), a core component of the m ⁶ A methyltransferase complex, not only functions as an m6A writer but also promotes tumorigenesis through m6A-independent mechanisms. Here, we show that METTL3 is mislocalized to the cytoplasm in breast cancer tumors from patients, contributing to the oncogenic phenotype. Cytoplasmic METTL3 interacts with EXOC7, a key exocytosis regulator. Additionally, METTL3 regulates m ⁶ A-dependent alternative splicing of EXOC7, promoting the expression of a more aggressive isoform. Silencing METTL3 impairs vesicle trafficking and the breast cancer secretome—effects that do not rely on its enzymatic activity but instead involve METTL3-mediated stabilization of EXOC7. Furthermore, METTL3 knockdown, but not inhibition of its catalytic function, impairs invadopodia formation, collagen matrix invasion, and focal adhesion morphology. Our findings uncover non-catalytic roles of METTL3 in regulating exocytosis and cancer secretome.