HER2Δ16剪接变体通过整合素驱动的信号促进乳腺癌转移

The HER2Δ16 splice variant, generated by exclusion of exon 16 from ERBB2 , is frequently detected in aggressive HER2-positive breast tumors and has been linked to enhanced tumorigenicity and therapy resistance. Unlike full-length HER2, HER2Δ16 forms constitutively active homodimers, yet the mechanisms driving its aggressive behavior remain poorly defined. Using isogenic models expressing full-length HER2 or HER2Δ16, we integrated cell surface proteomics with transcriptomic profiling to identify pathways uniquely altered by the splice variant. HER2Δ16 expression induced a wide range of cell-surface changes, including a striking enrichment of RGD-binding integrins. This remodeling was validated in HER2-positive patient tumors stratified for high versus low HER2Δ16 expression. HER2Δ16 cells displayed robust activation of the focal adhesion kinase (FAK) pathway and exhibited enhanced migration, invasion, and anchorage-independent growth. Functional perturbation studies demonstrated that HER2Δ16-driven aggressiveness requires integrin signaling. Integrin depletion or pharmacological inhibition of FAK significantly impaired motility, invasion, and growth in soft agar. In vivo , systemic FAK inhibition markedly reduced HER2Δ16 tumor growth and metastatic dissemination in immunodeficient mice, establishing integrin-FAK signaling as a therapeutic vulnerability associated with HER2Δ16 expression. These findings identify integrin-FAK signaling as a central effector of HER2Δ16-induced metastasis and reveal a previously unrecognized mechanism by which this splice variant rewires the adhesion landscape to promote invasive progression. Targeting integrin-driven signaling may provide a promising strategy to counteract metastatic dissemination in HER2Δ16-positive breast cancer.