Impact of Mechanical and Architectural Signals in the Tumor Microenvironment on Melanoma

Compared to sun-exposed melanomas, acral melanomas are genetically diverse and occur in areas with low sun exposure and high mechanical loads. During metastatic growth, melanomas invade from the epidermis to the dermis layers through dense tumor stroma and are exposed to fibrillar collagen architectures and mechanical stresses. However, the role of these signals during acral melanoma pathogenesis is not well understood. In this study, a novel 3D in vitro platform comprising heterogeneous, bundled collagen architectures recapitulates mechanical and architectural signals from the melanoma tumor microenvironment. YUSEEP patient-derived human acral melanoma and B16F10 mouse melanoma single cells and spheroids are embedded in collagen or bundled collagen hydrogels and mechanically compressed to quantitatively profile cellular responses to these cues, including viability, DNA damage and repair, proliferation, invasion, and nuclear and cellular morphologies. Spatial confinement of cells in a microfluidic platform, solid mechanics simulations, and pharmacological inhibition studies lend further mechanistic insights into these cues. Results reveal mechanical compression induces DNA damage and repair, while interactions with bundled collagen promote a malignant, protrusive phenotype. The findings further suggest that actin polymerization and contractility inhibitors may rescue DNA damage and mitigate malignancy upon compression, thereby potentially paving the way for novel therapeutic targets against acral melanomas.