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

// Hongwei Shao 1, * , Long Cai 1, 2, * , Mecker Moller 1 , Biju Issac 3 , Leiming Zhang 1, 4 , Mark Owyong 1 , Anna Elizabeth Moscowitz 1 , Roberto Vazquez-Padron 1 , Freddy Radtke 5 , Zhao-Jun Liu 1, 3 1 Department of Surgery, University of Miami School of Medicine, Miami, USA 2 Hangzhou Red-Cross Hospital, Zhejiang, China 3 Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA 4 Yantai University, School of Pharmacy, Shandong, China 5 Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland * These authors contributed equally to this work Correspondence to: Zhao-Jun Liu, email: zliu@med.miami.edu Keywords: cancer-associate fibroblasts, mesenchymal stem cells, Notch1, WISP-1/CCN4, melanoma Received: May 09, 2016 Accepted: October 26, 2016 Published: November 02, 2016 ABSTRACT 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-DF Notch1 −/− selectively promote, while MSC-DF N1IC+/+ preferentially suppress melanoma metastasis, but not growth, in mouse models. Consistently, conditioned media (CM) from MSC-DF Notch1 −/− and MSC-DF N1IC+/+ oppositely, yet selectively regulates migration, but not growth of melanoma cells in vitro . Additionally, when co-cultured with metastatic melanoma cells in vitro , MSC-DF Notch1 −/− support, while MSC-DF N1IC+/+ 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.