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

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.