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.
Highlights
Fibroblasts participate in the constitution of reactive tumor stroma [1]
In which the genetic activation or inactivation of Notch1 signaling occurs in natural host stromal fibroblasts, we showed that cancerassociated fibroblasts (CAF) carrying elevated Notch1 activity significantly inhibited melanoma growth and invasion, while those with a null Notch1 promoted melanoma invasion [15]
Notch1 activation did not appear to impact on phenotypic stability of Mesenchymal stem cells-derived fibroblasts (MSC-DF), since Cre-ires-GFP/Lentivirus-transduced cells were maintained as α-SMA+/vimentin+/FSP1+, so did GFP/Lentivirustransduced cells (Supplementary Figure S1, left)
Summary
Fibroblasts participate in the constitution of reactive tumor stroma [1]. They reside within tumor tissues and in the vicinity of tumor masses, referred to as cancerassociated fibroblasts (CAF). CAF take part in determining organ-specific metastases by preselecting a subset of tumor clones from heterogeneous tumor cell populations www.impactjournals.com/oncotarget in the primary lesion; fostering these selected clones to be primed for metastasis to a specific distant organ where its microenvironment is optimal for re-colonization of selected clones [6]. Their contribution to primary and secondary malignancies as well as taking part in drug resistance and tumor recurrence [7, 8] makes CAF potential therapeutic targets
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