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

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-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.

Intracellular Notch1 Signaling in Cancer-Associated Fibroblasts Dictates the Plasticity and Stemness of Melanoma Stem/Initiating Cells

“…3A). Consistently, MSC-DF Notch1−/− robustly increased lung metastasis [33]. These results indicate that turning "OFF" Notch1 signaling in MSC-DF promotes melanoma invasion and metastasis whereas turning "ON" Notch1 signaling in MSC-DF suppresses melanoma invasion and metastasis.…”

Clinical significance of miR-138 in patients with malignant melanoma through targeting of PDK1 in the PI3K/AKT autophagy signaling pathway

“…Control, control group; negative, negative control group; miR-138 mimics, miR-138 overexpression group; anti-PI3K, PI3K inhibitor (LY294002) and miR-138 overexpression group. biotherapy, radiotherapy and/or chemotherapy, although these methods have to date yielded unsatisfactory clinical effects on the prognosis and mortality rate of patients (21). In the present study the results revealed that miR-138 expression was significantly downregulated in patients with MM and the MM cell line A2058 when compared with normal controls.…”

WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial–mesenchymal transition

“…In this context, adjacent differentiated keratinocytes or endothelial cells are responsible for the cell surface Notch ligands, and neither Notch ligands nor active Notch signaling are detected in the stromal fibroblasts (70,71). Interestingly, when constitutively active Notch signaling was ectopically engineered into fibroblast cells by overexpressing a NOTCH1 intracellular domain (N IC ), WISP1 expression was elevated through increased transcription, suggesting that WISP1 is a downstream target of Notch signaling (50,51). Using engineered primary human dermal fibroblasts, Shao et al (50) showed in vivo, complemented by in vitro studies using conditioned media, that these cells repressed melanoma growth and angiogenesis but showed no effect on tumor migration.…”