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

Oncotarget. 2016 Nov 29;7(48):79262-79273. doi: 10.18632/oncotarget.13021.


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.

Keywords: Notch1; WISP-1/CCN4; cancer-associate fibroblasts; melanoma; mesenchymal stem cells.

MeSH terms

  • Animals
  • CCN Intercellular Signaling Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cells, Cultured
  • Coculture Techniques
  • Fibroblasts / cytology*
  • Fibroblasts / pathology
  • Humans
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / pathology
  • Mice
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins / metabolism*
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Signal Transduction
  • Tumor Microenvironment


  • CCN Intercellular Signaling Proteins
  • CCN4 protein, mouse
  • Notch1 protein, mouse
  • Proto-Oncogene Proteins
  • Receptor, Notch1