Notch1-WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis
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Hongwei Shao1,*, Long Cai1,2,*, Mecker Moller1, Biju Issac3, Leiming Zhang1,4, Mark Owyong1, Anna Elizabeth Moscowitz1, Roberto Vazquez-Padron1, Freddy Radtke5, Zhao-Jun Liu1,3
1Department of Surgery, University of Miami School of Medicine, Miami, USA
2Hangzhou Red-Cross Hospital, Zhejiang, China
3Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
4Yantai University, School of Pharmacy, Shandong, China
5Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland
*These authors contributed equally to this work
Zhao-Jun Liu, email: firstname.lastname@example.org
Keywords: cancer-associate fibroblasts, mesenchymal stem cells, Notch1, WISP-1/CCN4, melanoma
Received: May 09, 2016 Accepted: October 26, 2016 Published: November 02, 2016
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.
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