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Background <p>Lymphatic metastasis is strongly associated with poor prognosis. Although the chemokine receptor CCR7 is a well-established promoter of lymphatic dissemination, its prognostic relevance remains weak. We show that tumour cell plasticity, defined by podoplanin (PDPN)-expression and promoted by hypoxia, intersects with CCR7 function in triple-negative breast cancer (TNBC).</p> Methods <p>In vivo and in vitro studies using a CCR7-expressing TNBC mouse model were combined with transcriptomic profiling. Human relevance was assessed using scRNA-seq datasets from cell lines and primary tumours, as well as METABRIC breast cancer cohorts.</p> Results <p>A PDPN-defined tumour cell mesenchymal shift, promoted by hypoxia, was required for efficient CCR7-driven lymphatic metastasis and tumour progression. PDPN-expression was linked to tumour cell collagen-expression and suppression of interferon-signalling, features associated with an immune-cold microenvironment. PDPN-expression with effects on interferon and collagen programmes was observed across murine and human TNBC cell lines and correlated with hypoxia signatures in primary TNBC, mirroring murine findings. In METABRIC, a high combined CCR7–PDPN score predicted poor survival in lymph node–positive patients, whereas either marker alone lacked prognostic value.</p> Conclusions <p>PDPN is a tumour cell-associated biomarker of plasticity in TNBC, revealing synergy between hypoxia-induced mesenchymal phenotypic shifts and CCR7 in promoting lymphatic dissemination and poor prognosis.</p> <p></p>

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Podoplanin-defined tumour plasticity and CCR7-mediated lymphatic metastasis in triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Zhi Wang,
  • Lise Martine Ingebriktsen,
  • Tove Bekkhus,
  • Lyusong Ma,
  • Antonio Queiro-Palou,
  • Wenyang Shi,
  • Anastasia Bazioti,
  • Michail Angelos Panagias,
  • Martina Vigorelli,
  • Joakim Harry Lehrstrand,
  • Sarah Ring,
  • Anna Dimberg,
  • Elisabeth Wik,
  • Erling Andre Hoivik,
  • Jonas Fuxe,
  • Maria H. Ulvmar

摘要

Background

Lymphatic metastasis is strongly associated with poor prognosis. Although the chemokine receptor CCR7 is a well-established promoter of lymphatic dissemination, its prognostic relevance remains weak. We show that tumour cell plasticity, defined by podoplanin (PDPN)-expression and promoted by hypoxia, intersects with CCR7 function in triple-negative breast cancer (TNBC).

Methods

In vivo and in vitro studies using a CCR7-expressing TNBC mouse model were combined with transcriptomic profiling. Human relevance was assessed using scRNA-seq datasets from cell lines and primary tumours, as well as METABRIC breast cancer cohorts.

Results

A PDPN-defined tumour cell mesenchymal shift, promoted by hypoxia, was required for efficient CCR7-driven lymphatic metastasis and tumour progression. PDPN-expression was linked to tumour cell collagen-expression and suppression of interferon-signalling, features associated with an immune-cold microenvironment. PDPN-expression with effects on interferon and collagen programmes was observed across murine and human TNBC cell lines and correlated with hypoxia signatures in primary TNBC, mirroring murine findings. In METABRIC, a high combined CCR7–PDPN score predicted poor survival in lymph node–positive patients, whereas either marker alone lacked prognostic value.

Conclusions

PDPN is a tumour cell-associated biomarker of plasticity in TNBC, revealing synergy between hypoxia-induced mesenchymal phenotypic shifts and CCR7 in promoting lymphatic dissemination and poor prognosis.