Breast cancer remodels lymphatics in sentinel lymph nodes
: Eichin, Dominik; Lehotina, Diana; Kauko, Anni; Uenaka, Maki; Leppänen, Meri; Elima, Kati; Piipponen, Minna; Lönnberg, Tapio; Boström, Pia; Koskivuo, Ilkka; Aittokallio, Tero; Hollmén, Maija; Takeda, Akira; Jalkanen, Sirpa
Publisher: Springer Science and Business Media LLC
: 2025
: 10056
: 16
: 1
: 2041-1723
: 2041-1723
DOI: https://doi.org/10.1038/s41467-025-64981-z
: https://doi.org/10.1038/s41467-025-64981-z
: https://research.utu.fi/converis/portal/detail/Publication/505444130
Cancer metastasis to sentinel lymph nodes (LNs) is often the first marker of potential disease progression. Although it is recognized that tumor-induced lymphangiogenesis facilitates metastasis into LNs in murine models, tumor-induced alterations in human lymphatic vessels remain obscure. Here we use single-cell RNA sequencing and high-resolution spatial transcriptomics to profile lymphatic endothelial cell (LEC) subsets in paired metastatic and non-metastatic LNs obtained from female patients with treatment-naïve breast cancer. Tumor metastasis decreases immunoregulatory LEC subsets, such as PD-L1+ subcapsular sinus LECs, while inducing an increase in capillary-like CD200+ HEY1+ LECs. Matrix Gla protein (MGP) is the most upregulated gene in metastatic LN LECs, and its expression on LECs is TGF-β and VEGF dependent. Upregulated MGP promotes cancer cell adhesion to LN lymphatics. Thus, breast cancer cell metastasis to LNs remodels LEC subsets in human LNs and escalates MGP expression, potentially facilitating cancer cell dissemination through the lymphatic system.
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This work was financed by the Research Council of Finland (A.T., M.H. and S.J.), the Finnish Cancer Foundation (M.H. and S.J.), Sigrid Juselius Foundation (A.T., M.H. and S.J.), Jane and Aatos Erkko Foundation (S.J.) and Sakari Alhopuro Foundation (A.T. and D.E.). The Turku Bioscience Centre Single-cell Omics Core Facility, the Finnish Functional Genomics Centre and Biocenter Finland are acknowledged for infrastructure support.
