A1 Refereed original research article in a scientific journal
Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and beta 1-integrin activation
Authors: Pirita Pekkonen, Sanni Alve, Giuseppe Balistreri, Silvia Gramolelli, Olga Tatti-Bugaeva, Ilkka Paatero, Otso Niiranen, Krista Tuohinto, Nina Perälä, Adewale Taiwo, Nadezhda Zinovkina, Pauliina Repo, Katherine Icay, Johanna Ivaska, Pipsa Saharinen, Sampsa Hautaniemi, Kaisa Lehti, Päivi M Ojala
Publisher: ELIFE SCIENCES PUBLICATIONS LTD
Publication year: 2018
Journal: eLife
Journal name in source: ELIFE
Journal acronym: ELIFE
Article number: e32490
Volume: 7
Number of pages: 28
ISSN: 2050-084X
eISSN: 2050-084X
DOI: https://doi.org/10.7554/eLife.32490
Web address : https://elifesciences.org/articles/32490
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/31772056
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 beta 1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident beta 1-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.
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