Cancer-associated fibroblasts derived amphiregulin promotes HNSCC progression and drug resistance of EGFR inhibitor

In clinical oncology, lack of sustained treatment response is very common in cancer patients and largely limits the efficiency of most anticancer targeted-therapies. While anti-EGFR therapeutics have been extensively employed in head and neck squamous cell carcinoma (HNSCC) management, their clinical efficacy remains limited due to unresolved resistance mechanisms. Notably, the functional role of EGFR ligand proteins in both tumor progression and therapeutic response has not been fully elucidated. Here we reveal that amphiregulin (AREG) as a potential driver of drug resistance of EGFR-targeted treatment in HNSCC patients. We identify a PDGFRβ⁺FAP⁺αSMA⁺ myofibroblast (myCAF) subset as the major source of AREG in tumor microenvironment. TCGA database and clinical cohort demonstrated that patients with high AREG expression exhibited significantly higher lymph node metastasis rates (59.35 %) and poorer prognosis (median 5-year survival: 2.2 years). In contrast, patients with low AREG expression showed reduced metastatic potential (metastasis rate: 45.16 %) and more favorable clinical outcomes (median 5-year survival: 4.8 years). Mechanistically, AREG promotes vascular mimicry formation via epithelial-endothelial transition of tumor cells to offer extra blood supply and metastasis channels. Further, live-cell imaging revealed that AREG induces plasma membrane stabilization of over 90 % receptor proteins while concurrently enhancing receptor recycling, driving EGFR inhibitor resistance. Collectively, our study reveals the crucial role of AREG in tumor landscape, informing a new predictive biomarker of EGFR inhibitor efficiency as well as a new potential therapeutic target of HNSCC.