Amphiregulin (AREG)

• Radiation-induced amphiregulin drives tumour metastasis
• Motor neurons and endothelial cells additively promote development and fusion of human iPSC-derived skeletal myocytes
• Amphiregulin blockade decreases the levodopa-induced dyskinesia in a 6-hydroxydopamine Parkinson's disease mouse model
• Droplet-based forward genetic screening of astrocyte-microglia cross-talk
• Knockdown of Amphiregulin Triggers Doxorubicin-Induced Autophagic and Apoptotic Death by Regulating Endoplasmic Reticulum Stress in Glioblastoma Cells
• Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer
• Circulating Tumor Biomarkers in Meningiomas Reveal a Signature of Equilibrium Between Tumor Growth and Immune Modulation
• Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells

Amphiregulin (AREG) is a transmembrane glycoprotein and a member of the epidermal growth factor (EGF) family. It functions primarily as a ligand for the epidermal growth factor receptor (EGFR).

• Protein type: Transmembrane, EGF-like growth factor
• Gene: AREG (Chromosome 4q13.3)
• Activation: Cleaved by metalloproteases (e.g., ADAM17) to release soluble form
• Receptor binding: Binds EGFR (ErbB1/HER1)

• Promotes cell proliferation, survival, and migration
• Involved in organ development (lung, mammary gland)
• Key role in wound healing and epithelial regeneration
• Modulates immune responses and inflammation

AREG is frequently upregulated in various cancers and is associated with:

• Tumor growth and progression
• Metastasis induction
• Resistance to EGFR-targeted therapies
• Immunosuppressive tumor microenvironment

• Reference: Nature, 2025 May 14. Piffkó et al.

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• Title: Radiation-induced amphiregulin drives tumour metastasis
• Main result: Radiotherapy induces AREG expression in tumor cells, which activates EGFR on myeloid cells → immunosuppression and reduced phagocytosis, facilitating distant metastasis.
• Therapeutic implication: Combining radiotherapy with AREG/EGFR inhibitor may improve metastatic control.

• EGFR → RAS/RAF/MEK/ERK → Proliferation
• EGFR → PI3K/AKT/mTOR → Survival
• EGFR → JAK/STAT → Immune modulation

• Biomarker for aggressiveness and therapy resistance
• Target for combination therapy with radiotherapy
• May guide patient stratification for EGFR blockade

Radiotherapy (RT) is a key modality in cancer treatment, traditionally associated with local tumor control and systemic immune activation (e.g., the abscopal effect). However, the pro-metastatic potential of RT is underexplored.

This study identifies amphiregulin (AREG) as a critical factor induced by RT that promotes distant metastasis by reprogramming EGFR-positive myeloid cells into an immunosuppressive phenotype.

• RT induces expression of AREG in tumor cells.
• AREG acts on EGFR-expressing myeloid cells, inhibiting phagocytosis.
• This reprogramming suppresses immune surveillance and supports distant metastatic outgrowth.
• Inhibition of AREG or EGFR reduces metastasis in preclinical models.

• Mechanistic insight: RT ➝ AREG ➝ EGFR+ myeloid cells ➝ immunosuppression ➝ metastasis.
• Multimodal design: Combines in vitro, in vivo, and clinical observations.
• Translational relevance: Suggests therapeutic potential of AREG or EGFR blockade post-RT.
• Paradigm shift: Challenges the assumption that RT is solely antitumoral.

• Tumor heterogeneity not addressed: Unclear whether the mechanism is universal across tumor types.
• Simplified immunological view: Focuses on myeloid cells; limited analysis of T-cell responses.
• Lacks clinical trial data: Proposes interventions not yet validated in humans.
• Short-term perspective: No data on long-term effects of AREG inhibition (e.g., on wound healing).
• Potential oversimplification: Other radiation-induced cytokines may also contribute to metastasis.

• Reframes RT as a double-edged sword: antitumoral locally, potentially protumoral systemically.
• Encourages exploration of RT + anti-EGFR/anti-AREG combinations.
• Reinforces the importance of immune monitoring during radiotherapy.

This study presents robust evidence that RT can promote metastasis via radiation-induced AREG, which suppresses innate immunity. It introduces a compelling mechanism with therapeutic and conceptual implications, though further clinical validation is needed.

• Amphiregulin (AREG)
• EGFR Pathway
• Immune Evasion
• Radiotherapy
• Combination Therapy