TGF-α/EGFR-mediated lymphatic metastasis reveals a repositionable therapeutic target in breast cancer

Cancer research · Breast cancer · EGFR

Here, we demonstrate that EGFR promotes selective lymphatic dissemination in triple-negative breast cancer through a chemotactic mechanism involving the EGFR ligand TGF-α.

The epidermal growth factor receptor (EGFR) is a well-established oncogenic driver in multiple epithelial cancers, yet its role in breast cancer remains elusive, with EGFR-targeted therapies showing limited clinical efficacy. Here, we demonstrate that EGFR promotes selective lymphatic dissemination in triple-negative breast cancer through a chemotactic mechanism involving the EGFR ligand TGF-α. Lymphatic endothelial cells (LECs) were identified as a tumor‑associated source of TGF‑α, both in a murine model and in human breast cancer, particularly upon stimulation with TGF‑β1, a cytokine commonly overexpressed in breast tumors associated with lymph metastasis. We found that TGF‑α/EGFR interactions elicit directional migration via STAT3 signaling, whereas the co‑secreted ligand CTGF, enriched in blood endothelial cells, suppressed migration. Pharmacologic blockade of TGF‑α with Fepixnebart, a first‑in‑class ligand‑neutralizing antibody targeting TGF‑α and previously not tested in oncologic indications, significantly inhibited early lymph metastasis of EGFR+ tumor cells. Furthermore, EGFR overexpression resulted in increased cellularity in tumor‑draining lymph nodes and reduced CD8+ T‑cell representation. Together, these findings reveal a role for the TGF‑α/EGFR axis in lymph metastasis and propose a rationale for repositioning EGFR-targeted therapies toward targeting early metastatic spread and immunomodulation in breast cancer.

Evidence level: Állatkísérletes. Állatmodellben vizsgálták.

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