PUBLICATION
Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and ?1-integrin activation
- 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.
- ID
- ZDB-PUB-180502-15
- Date
- 2018
- Source
- eLIFE 7: (Journal)
- Registered Authors
- Ivaska, Johanna, Paatero, Ilkka, Perälä, Nina
- Keywords
- MMP14, Notch, cancer biology, cell biology, human, integrin, lymphatic endothelial cell, melanoma, metastasis, mouse, zebrafish
- MeSH Terms
-
- Humans
- Mice
- Neoplasm Invasiveness
- Apoptosis
- Female
- Zebrafish
- Liver Neoplasms/metabolism
- Liver Neoplasms/secondary*
- Cell Movement
- Integrin beta1/metabolism*
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology*
- Receptor, Notch3/metabolism*
- Endothelium, Lymphatic/metabolism
- Endothelium, Lymphatic/pathology*
- Cell Proliferation
- Lymphatic Metastasis
- Mice, SCID
- Xenograft Model Antitumor Assays
- Animals
- Matrix Metalloproteinase 14/metabolism*
- Cells, Cultured
- Lung Neoplasms/metabolism
- Lung Neoplasms/secondary*
- PubMed
- 29712618 Full text @ Elife
Citation
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. (2018) Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and ?1-integrin activation. eLIFE. 7.
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 ?1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident ?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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping