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

Pekkonen, Pirita, Alve, Sanni, Balistreri, Giuseppe, Gramolelli, Silvia, Tatti-Bugaeva, Olga, Paatero, Ilkka, Niiranen, Otso, Tuohinto, Krista, Perälä, Nina, Taiwo, Adewale, Zinovkina, Nadezhda, Repo, Pauliina, Icay, Katherine, Ivaska, Johanna, Saharinen, Pipsa, Hautaniemi, Sampsa, Lehti, Kaisa, Ojala, Päivi M·2018·eLife

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.

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  • MT1-MMP is highly expressed in various types of cancer cells and promotes cancer metastasis and angiogenesis.

    “It is well documented that MT1-MMP is highly expressed in various types of cancer cells and promotes cancer metastasis and angiogenesis16,44,47–50.”

    From Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis (2021) · cites this paper as [49]

    The Results section reports that MMP14 (MT1-MMP) is frequently induced in invasive melanoma and that high expression correlates with melanoma progression and metastasis. The Discussion links MMP14 to invasive behavior but cautions that high MMP14 alone was not sufficient for distant metastasis. The paper does not establish high expression across various cancer types or show that MMP14 promotes angiogenesis; the angiogenesis passages concern other mechanisms or an assay adapted for this study. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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Metadata

Authors
Pekkonen, P., Alve, S., Balistreri, G., Gramolelli, S., Tatti-Bugaeva, O., Paatero, I., Niiranen, O., Tuohinto, K., Perälä, N., Taiwo, A., Zinovkina, N., Repo, P., Icay, K., Ivaska, J., Saharinen, P., Hautaniemi, S., Lehti, K., & Ojala, P. M.
Venue
eLife
Published
2018-05-01
Volume
7
ISSN
2050-084X
Cited by
42
References
1
Language
en
Funders
  • Terveyden Tutkimuksen Toimikunta (307366, 309544)
  • Finnish Cancer Foundation
  • Sigrid Juséliuksen Säätiö
  • University of Helsinki (Doctoral program in Biomedicine)
  • University of Helsinki Foundation
  • Suomen Lääketieteen Säätiö
  • Emil Aaltosen Säätiö

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