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Elife. 2018 May 1;7. pii: e32490. doi: 10.7554/eLife.32490.

Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and β1-integrin activation.

Author information

1
Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
2
Genome-Scale Biology, University of Helsinki, Helsinki, Finland.
3
Turku Centre for Biotechnology, University of Turku, Turku, Finland.
4
Department of Biochemistry, University of Turku, Turku, Finland.
5
Wihuri Research Institute, Helsinki, Finland.
6
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
7
Foundation for the Finnish Cancer Institute, Helsinki, Finland.
8
Section of Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
#
Contributed equally

Abstract

Lymphatic invasion and lymph node metastasis correlate with poor clinical outcome in melanoma. However, the mechanisms of lymphatic dissemination in distant metastasis remain incompletely understood. We show here that exposure of expansively growing human WM852 melanoma cells, but not singly invasive Bowes cells, to lymphatic endothelial cells (LEC) in 3D co-culture facilitates melanoma distant organ metastasis in mice. To dissect the underlying molecular mechanisms, we established LEC co-cultures with different melanoma cells originating from primary tumors or metastases. Notably, the expansively growing metastatic melanoma cells adopted an invasively sprouting phenotype in 3D matrix that was dependent on MMP14, Notch3 and β1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident β1-integrin activation. Moreover, MMP14 and Notch3 were required for LEC-mediated metastasis of zebrafish xenografts. This study uncovers a unique mechanism whereby LEC contact promotes melanoma metastasis by inducing a reversible switch from 3D growth to invasively sprouting cell phenotype.

KEYWORDS:

MMP14; Notch; cancer biology; cell biology; human; integrin; lymphatic endothelial cell; melanoma; metastasis; mouse; zebrafish

Conflict of interest statement

PP, SA, GB, SG, OT, IP, ON, KT, NP, AT, NZ, PR, KI, JI, PS, SH, KL, PO No competing interests declared

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