Notch1-WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis.
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 co-grafted 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.
Department of Surgery, University of Miami School of Medicine, Miami, USA.
Hongwei
H
Shao
Department of Surgery, University of Miami School of Medicine, Miami, USA.|Hangzhou Red-Cross Hospital, Zhejiang, China.
Long
L
Cai
Department of Surgery, University of Miami School of Medicine, Miami, USA.
Mecker
M
Moller
Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
Biju
B
Issac
Department of Surgery, University of Miami School of Medicine, Miami, USA.|Yantai University, School of Pharmacy, Shandong, China.
Leiming
L
Zhang
Department of Surgery, University of Miami School of Medicine, Miami, USA.
Mark
M
Owyong
Department of Surgery, University of Miami School of Medicine, Miami, USA.
Anna Elizabeth
AE
Moscowitz
Department of Surgery, University of Miami School of Medicine, Miami, USA.
Roberto
R
Vazquez-Padron
Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
Freddy
F
Radtke
Department of Surgery, University of Miami School of Medicine, Miami, USA.|Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
Zhao-Jun
ZJ
Liu
D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D005347:Fibroblasts / Q000166:cytology* / Q000473:pathology; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment
D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; C497762:Notch1 protein, mouse; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1
Notch1; WISP-1/CCN4; cancer-associate fibroblasts; melanoma; mesenchymal stem cells