Breast cancer remodels lymphatics in sentinel lymph nodes

Dominik Eichin; Diana Lehotina; Anni Kauko; Maki Uenaka; Meri Leppänen; Kati Elima; Minna Piipponen; Tapio Lönnberg; Pia Boström; Ilkka Koskivuo; Tero Aittokallio; Maija Hollmén; Akira Takeda; Sirpa Jalkanen

doi:10.1038/s41467-025-64981-z

Breast cancer remodels lymphatics in sentinel lymph nodes

Dominik Eichin
, Diana Lehotina
, Anni Kauko
, Maki Uenaka
, Meri Leppänen
, Kati Elima
, Minna Piipponen
, Tapio Lönnberg
, Pia Boström
, Ilkka Koskivuo
, Tero Aittokallio
, Maija Hollmén
, Akira Takeda^*
, Sirpa Jalkanen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

5 Citations (Scopus)

85 Downloads (Pure)

Abstract

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.

Original language	English
Article number	10056
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-64981-z
Publication status	Published - Dec 2025
MoE publication type	A1 Journal article-refereed

Funding

We thank Teppo Huttunen from Estimates for statistical analyses, Sari Mäki and Riikka Sjöroos for technical help, Joe Hettinger for revising the language, Bishwa Ghimire for his advice on bioinformatic analyses, Dinghao Zheng for running the Space Ranger pipeline, Damien Kaukonen for running the Space Ranger pipeline and statistical consultation, and Prof. Kari Alitalo for providing us with the anti-VEGFR3 antibody. 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.

Access to Document

10.1038/s41467-025-64981-zLicence: CC BY

s41467-025-64981-zFinal published version, 7.72 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe202601279143

Cite this

@article{9a0ebefe77d34208a39a7387e4c2c8ef,

title = "Breast cancer remodels lymphatics in sentinel lymph nodes",

abstract = "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-na{\"i}ve 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.",

keywords = "Breast cancer, Lymphatic vessels, Lymph node",

author = "Dominik Eichin and Diana Lehotina and Anni Kauko and Maki Uenaka and Meri Lepp{\"a}nen and Kati Elima and Minna Piipponen and Tapio L{\"o}nnberg and Pia Bostr{\"o}m and Ilkka Koskivuo and Tero Aittokallio and Maija Hollm{\'e}n and Akira Takeda and Sirpa Jalkanen",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-64981-z",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Breast cancer remodels lymphatics in sentinel lymph nodes

AU - Eichin, Dominik

AU - Lehotina, Diana

AU - Kauko, Anni

AU - Uenaka, Maki

AU - Leppänen, Meri

AU - Elima, Kati

AU - Piipponen, Minna

AU - Lönnberg, Tapio

AU - Boström, Pia

AU - Koskivuo, Ilkka

AU - Aittokallio, Tero

AU - Hollmén, Maija

AU - Takeda, Akira

AU - Jalkanen, Sirpa

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Lymphatic vessels

KW - Lymph node

UR - https://www.scopus.com/pages/publications/105021980210

U2 - 10.1038/s41467-025-64981-z

DO - 10.1038/s41467-025-64981-z

M3 - Article

C2 - 41249124

AN - SCOPUS:105021980210

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 10056

ER -

Breast cancer remodels lymphatics in sentinel lymph nodes

Abstract

Funding

Access to Document

Other files and links

Fingerprint

Cite this