SNAI1 ablation alters integrin-mediated adhesion and endocytic fate

Using a complete SNAI1 knockout in mesenchymal, triple-negative breast cancer cells, unbiased genome-wide transcriptomic analysis revealed a marked under-expression of integrin-based adhesion and endocytic components. Utilizing this knockout cell model, complementary breast cancer cell models and functional screening of multiple differentially expressed genes, we found that the pioneering transcription factor FOXA1, whose expression is repressed by SNAI1, associates with several key mediators of the cellular phenotype.

FOXA1 represses the small GTPase ARF6 and its exchange factor PSD4, in addition to integrin and matrix metalloprotease genes. Accordingly, SNAI1 knockout cells presented poor adhesion to collagen type I or fibronectin, formed defective invadopodia and focal adhesions with weakened FAK/SRC signaling. SNAI1 knockout cells performed ineffective receptor-mediated internalization, including nanoparticle and extracellular vesicle (EV) uptake, exhibited reduced lysosomal content, lacked multivesicular bodies enriched in intraluminal vesicles and showed decreased EV secretion.