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ResearchIn-Press PreviewCell biologyVascular biology Open Access | 10.1172/jci.insight.171821

DLL4-Notch3-WNT5B axis mediates bi-directional pro-metastatic crosstalk between melanoma and lymphatic endothelial cells

Sanni Alve,1 Silvia Gramolelli,2 Joonas Jukonen,1 Susanna Juteau,3 Anne Pink,1 Atte A. Manninen,4 Satu Hänninen,3 Elisa Monto,1 Madeleine H. Lackman,5 Olli Carpén,6 Pipsa Saharinen,7 Sinem Karaman,5 Kari Vaahtomeri,1 and Päivi M. Ojala1

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Alve, S. in: JCI | PubMed | Google Scholar

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Gramolelli, S. in: JCI | PubMed | Google Scholar |

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Jukonen, J. in: JCI | PubMed | Google Scholar |

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Juteau, S. in: JCI | PubMed | Google Scholar

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Pink, A. in: JCI | PubMed | Google Scholar

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Manninen, A. in: JCI | PubMed | Google Scholar

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Hänninen, S. in: JCI | PubMed | Google Scholar |

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Monto, E. in: JCI | PubMed | Google Scholar |

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Lackman, M. in: JCI | PubMed | Google Scholar |

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Carpén, O. in: JCI | PubMed | Google Scholar

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Saharinen, P. in: JCI | PubMed | Google Scholar |

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Karaman, S. in: JCI | PubMed | Google Scholar |

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Vaahtomeri, K. in: JCI | PubMed | Google Scholar |

1Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland

2Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

3Department of Pathology, Helsinki University Hospital (HUS), University of Helsinki, Helsinki, Finland

4Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

5Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland

6Translational Cancer Research, University of Helsinki, Helsinki, Finland

7Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

Find articles by Ojala, P. in: JCI | PubMed | Google Scholar |

Published November 16, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.171821.
Copyright © 2023, Alve et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 16, 2023 - Version history
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Abstract

Despite strong indications that melanoma interaction with lymphatic vessels actively promotes 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) co-cultures with human melanoma cell lines. Here, we show that co-culture with melanoma cells induced transcriptomic changes in LECs and led to multiple alterations in their function. WNT5B, a paracrine signaling molecule upregulated in melanoma cells upon LEC interaction, was found contributing to the functional changes in LECs. Moreover, WNT5B transcription was regulated by Notch3 in melanoma cells following the co-culture with LECs, and Notch3 and WNT5B were coexpressed in melanoma patient primary tumor and metastasis samples. Moreover, melanoma cells derived from LEC co-culture 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 bi-directional crosstalk between melanoma cells and lymphatic endothelium and promoting melanoma metastasis.

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