Phenotypic switch and reduced the growth of melanoma spheroids in the presence of mast cell-conditioned medium: potential impact of nutrient starvation effects

Mast cells are abundant in melanoma tumors, and studies suggest that they can be either detrimental or protective for melanoma growth. However, the underlying mechanisms are not fully understood. Here, we adopted a hanging drop-established spheroid system to investigate how mast cells can influence melanoma growth and phenotype in a 3-D context. In the presence of mast cells or mast cell-conditioned medium, melanoma spheroid growth was profoundly reduced. To address the underlying mechanism, we conducted a transcriptomic analysis, which revealed that mast cell-conditioned medium had extensive effects on the melanoma gene expression patterns. Pathway analyses revealed profound effects on the expression of genes related to amino acid and protein metabolism. The conditioned medium also induced an upregulated expression of cancer-related genes, including adhesion molecules implicated in metastatic spreading. In line with this, after transfer to a Matrigel extracellular matrix milieu, spheroids that had been developed in the presence of mast cell-conditioned medium displayed enhanced elevated growth and adhesive properties. However, when assessing for possible effects of nutrient starvation, i.e., reduced nutrient content in mast cell-conditioned medium, we found that the observed effects on melanoma spheroid growth potentially could be explained by such effects. Hence, it cannot be excluded that the observed phenotypic alterations of melanoma spheroids grown in the presence of mast cells or mast cell-conditioned media are, at least partly, due to nutrient starvation rather than to the action of factors secreted by mast cells. Instead, our findings may provide insight into the effects on gene expression events that occur in melanoma tumors under nutrient stress.