DLL4/Notch3/WNT5B axis mediates bidirectional prometastatic crosstalk between melanoma and lymphatic endothelial cells.

Autor: Alve S; Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Gramolelli S; Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland., Jukonen J; Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Juteau S; Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland., Pink A; Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Manninen AA; Department of Plastic Surgery, Park Hospital, Helsinki University Hospital (HUS), and., Hänninen S; Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland., Monto E; Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Lackman MH; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Carpén O; Helsinki Biobank, and.; Department of Pathology and Research Program in Systems Oncology, University of Helsinki, HUS Diagnostic Center, Helsinki University Hospital, Finland., Saharinen P; Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Wihuri Research Institute, Biomedicum, Helsinki, Finland.; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Karaman S; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Wihuri Research Institute, Biomedicum, Helsinki, Finland., Vaahtomeri K; Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Wihuri Research Institute, Biomedicum, Helsinki, Finland., Ojala PM; Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 Jan 09; Vol. 9 (1). Date of Electronic Publication: 2024 Jan 09.
DOI: 10.1172/jci.insight.171821
Abstrakt: Despite strong indications that interactions between melanoma and lymphatic vessels actively promote melanoma progression, the molecular mechanisms are not yet completely understood. To characterize molecular factors of this crosstalk, we established human primary lymphatic endothelial cell (LEC) cocultures with human melanoma cell lines. Here, we show that coculture with melanoma cells induced transcriptomic changes in LECs and led to multiple changes in their function. WNT5B, a paracrine signaling molecule upregulated in melanoma cells upon LEC interaction, was found to contribute to the functional changes in LECs. Moreover, WNT5B transcription was regulated by Notch3 in melanoma cells following the coculture with LECs, and Notch3 and WNT5B were coexpressed in melanoma patient primary tumor and metastasis samples. Moreover, melanoma cells derived from LEC coculture escaped efficiently from the primary site to the proximal tumor-draining lymph nodes, which was impaired upon WNT5B depletion. This supported the role of WNT5B in promoting the metastatic potential of melanoma cells through its effects on LECs. Finally, DLL4, a Notch ligand expressed in LECs, was identified as an upstream inducer of the Notch3/WNT5B axis in melanoma. This study elucidated WNT5B as a key molecular factor mediating bidirectional crosstalk between melanoma cells and lymphatic endothelium and promoting melanoma metastasis.
Databáze: MEDLINE
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