Characterization of the Multifaceted Roles of sFRP1 in Melanoma: Investigations into WNT Signalling and Phenotypic Modulation

Abstract

Melanoma is an aggressive form of skin cancer that is commonly characterized by frequent metastasis and acquisition of therapeutic resistance. While early-stage treatment offers favourable outcomes, the prognosis for advanced disease remains poor. Recently, secreted Frizzled-Related Proteins (sFRPs) have been identified to exert nuanced roles in various cancers. For instance, the most well-studied of the family group, sFRP1, is strongly implicated as a tumour suppressor in colorectal cancer, though conversely, promotes tumour development in prostate cancer. Although its role is established in other cancers, the precise mechanism of sFRP1s contribution towards melanoma progression remains underexplored. Within our lab, preliminary evidence suggests that sFRP1 positively correlates with poor patient outcomes, including poor overall and distant metastasis free survival, and has found elevated expression of sFRP1 in metastases. As such, we hypothesized that sFRP1 promotes migratory and invasive phenotypes, while reducing proliferation, through modulation of Wnt signalling pathways. Results revealed distinct expression levels of sFRP1, Wnt ligands, and Wnt receptors across cell lines, indicative of unique environmental niches. Furthermore, sFRP1 demonstrated cell-line-specific effects over Wnt signalling mediators, likely driven by variations in local ligand-receptor availability, that further manifested as cell-line specific impacts over melanoma cell behaviours. Notably, sFRP1 decreased proliferation of cells cultured in non-adherent conditions, and decreased invasion, and migration in the B16F10 cell line. Intriguingly, preliminary data revealed that sFRP1 upregulates PD-L1 expression in B16F10 cells, representing the first reported association between sFRPs and immune checkpoint regulation in melanoma. These findings suggest a multifaceted role for sFRP1 in melanoma progression, including potential contributions to immune modulation, warranting further mechanistic exploration.