Notch signaling mediates melanoma–endothelial cell communication and melanoma cell migration

Abstract

Stromal and cellular components within the tumor microenvironment significantly influence molecular signals mediating tumor growth and progression. We recently performed a screen to evaluate critical mediators of melanoma-endothelial communication and identified several molecular pathways associated with these cellular networks, including Notch3. Here, we evaluate the nature of melanoma-endothelial communication mediated by Notch3 and its functional significance. We find that Notch3 is specifically upregulated in melanoma-endothelial cell cocultures and is functionally associated with increased Notch signaling in melanoma cells. Furthermore, induced Notch3 signaling in melanoma cell lines leads to enhanced tumor cell migration without associated increases in tumor cell growth. Additionally, Notch3 expression is specifically associated with malignant patient samples and is not evident in benign nevi. We conclude that Notch3 mediates melanoma-endothelial cell communication and tumor cell migration and may serve as a meaningful therapeutic target for this aggressive malignancy.

Interactions of Melanoma Cells with Distal Keratinocytes Trigger Metastasis via Notch Signaling Inhibition of MITF

“…Remarkably, expression of some Notch ligands was detectable only in the upper layer of the epidermis ( Figures 2B and S2C). Endothelial cells served as an internal positive control (Howard et al, 2013). Accordingly, Notch activity, as indicated by the presence of nuclear NICD, was observed similarly only in the upper epidermis ( Figure S2D) in line with a previous study (Watt et al, 2008).…”

“…To investigate this model, melanoma cells with no intrinsic invasive abilities (Figure S1A) (Levy et al, 2010) were co-cultured (in 1:5 ratio) with primary cells characterizing human skin: differentiated keratinocytes, basal keratinocytes, fibroblasts, or endothelial cells, and then invasion capability was analyzed using an in vitro matrigel invasion assay ( Figure 1A). Co-culture with dermal endothelial cells served as a positive control (Howard et al, 2013). Remarkably, melanoma cells gained significant invasion ability following co-culture with differentiated keratinocytes, (p < 0.05).…”

Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features

“…(31, 32) The Notch pathway has been shown in other malignancies to interact with various components of the tumor microenvironment including endothelial cells, stroma and secreted molecules. (31, 33–35) The significant association of non-peripheral NICD1 expression with high-risk features in our study implies that dysregulation of NOTCH1-mediated communication of HNSCC tumors cells with the surrounding microenvironment may be a determinant of disease progression.…”

Developmental pathways activated in melanocytes and melanoma

“…The function of Notch3 in melanoma development is intriguing. In one study, a screen was performed to identify important mediators of melanoma-endothelial communication and Notch3 was found to be upregulated in melanoma cells co-cultured with endothelial cells, which activates Notch signaling in melanoma cells (Howard et al, 2013). Activated Notch3 signaling is associated with enhanced melanoma cell migration without affecting tumor cell growth.…”