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
MediCity Research Laboratory, University of Turku, Turku, Finland.
InFLAMES Flagship, University of Turku, Turku, Finland.
Nat Commun. 2025 Nov 17;16(1):10056. doi: 10.1038/s41467-025-64981-z.
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.
癌症转移至前哨淋巴结通常是疾病潜在进展的首个标志。尽管在小鼠模型中已认识到肿瘤诱导的淋巴管生成促进了肿瘤细胞转移至淋巴结，但肿瘤诱导的人类淋巴管改变仍不清楚。在此，我们使用单细胞RNA测序和高分辨率空间转录组学来分析从未经治疗的女性乳腺癌患者获取的配对转移性和非转移性淋巴结中的淋巴管内皮细胞（LEC）亚群。肿瘤转移减少了免疫调节性LEC亚群，如PD-L1被膜下窦LEC，同时诱导毛细血管样CD200 HEY1 LEC增加。基质Gla蛋白（MGP）是转移性淋巴结LEC中上调最明显的基因，其在LEC上的表达依赖于转化生长因子-β（TGF-β）和血管内皮生长因子（VEGF）。上调的MGP促进癌细胞与淋巴结淋巴管的黏附。因此，乳腺癌细胞转移至淋巴结会重塑人类淋巴结中的LEC亚群并上调MGP表达，这可能会促进癌细胞通过淋巴系统播散。
