While previous studies have explored the mechanistic role of ASPN in other cancer-related pathways, including CD44 (37), TGF-β (34), and EGFR (79), to the best of our knowledge, our study is the first to report extracellular ASPN directly binds to HER3 and activates signaling through heterodimerization with HER2. This evidence concerns the gene ERBB2 and cancer.