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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月3日

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  • Wenyang Shi,
  • Yueyun Pan,
  • Bhavik Rathod,
  • Yuhan Wang,
  • Zhi Wang,
  • Jianyu Shen,
  • Francesca Gatto,
  • Mingzhi Liu,
  • Yizhe Sun,
  • Margareta Wilhelm,
  • Thomas Helleday,
  • Maria H. Ulvmar,
  • Sara H. Windahl,
  • Mikael C. I. Karlsson,
  • Jonas Fuxe

摘要

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.