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  4. Notch1-WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis
 
research article

Notch1-WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis

Shao, Hongwei
•
Cai, Long
•
Moller, Mecker
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2016
Oncotarget

Mesenchymal stem cells-derived fibroblasts (MSC-DF) constitute a significant portion of stromal fibroblasts in the tumor microenvironment (TME) and are key modulators of tumor progression. However, the molecular mechanisms that determine their tumor-regulatory function are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that selectively controls the regulatory role of MSC-DF in melanoma metastasis. We demonstrate that the Notch1 pathway's activity is inversely correlated with the metastasis-regulating function of fibroblasts and can determine the metastasis-promoting or-suppressing phenotype of MSC-DF. When cografted with melanoma cells, MSC-DFNotch1-/- selectively promote, while MSC-DFN1IC+/+ preferentially suppress melanoma metastasis, but not growth, in mouse models. Consistently, conditioned media (CM) from MSC-DFNotch1-/- and MSC-DFN1IC+/+ oppositely, yet selectively regulates migration, but not growth of melanoma cells in vitro. Additionally, when co-cultured with metastatic melanoma cells in vitro, MSC-DFNotch1-/- support, while MSC-DFN1IC+/+ inhibit melanoma cells in the formation of spheroids. These findings expand the repertoire of Notch1 signaling as a molecular switch in determining the tumor metastasis-regulating function of MSC-DF. We also identified Wnt-induced secreted protein-1 (WISP-1) as a key downstream secretory mediator of Notch1 signaling to execute the influential role of MSC-DF on melanoma metastasis. These findings reveal the Notch1-WISP-1 axis as a crucial molecular determinant in governing stromal regulation of melanoma metastasis; thus, establishing this axis as a potential therapeutic target for melanoma metastasis.

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Type
research article
DOI
10.18632/oncotarget.13021
Web of Science ID

WOS:000389636000084

Author(s)
Shao, Hongwei
Cai, Long
Moller, Mecker
Issac, Biju
Zhang, Leiming
Owyong, Mark
Moscowitz, Anna Elizabeth
Vazquez-Padron, Roberto
Radtke, Freddy  
Liu, Zhao-Jun
Date Issued

2016

Publisher

Impact Journals Llc

Published in
Oncotarget
Volume

7

Issue

48

Start page

79262

End page

79273

Subjects

cancer-associate fibroblasts

•

mesenchymal stem cells

•

Notch1

•

WISP1/CCN4

•

melanoma

Editorial or Peer reviewed

REVIEWED

Written at

OTHER

EPFL units
UPRAD  
Available on Infoscience
January 24, 2017
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/133608
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