By Julian Namerow, Class of 2026
Melanomas are deadly skin cancers, with certain subtypes carrying an 80% mortality rate because they respond poorly to immune-, radio-, and chemotherapy treatments. Sun-exposed melanomas are a highly prevalent melanoma variant that cause DNA damage and mutation. However, acral melanomas are genetically diverse and occur in areas with low sun exposure and high mechanical loads due to physical pressure. Commonly affected areas include the palms of the hands and feet, which are subjected to mechanical stress from walking. In the dermis, melanomas invade surrounding tissue, proliferate, and are exposed to extracellular collagen architectures and mechanical stresses. The role that these environmental cues play in acral melanomas is not understood. Since acral melanomas develop on the rear and front regions of plantar surfaces subjected to high pressures, like the soles of one’s feet, this suggests that mechanical stresses likely contribute to the formation of acral melanomas.
The mechanical resistance of a confined microenvironment on moving and metastasizing cancer cells alters the extracellular matrix topography and stiffens it. The stiffening extracellular space surrounding the tumor can influence its migration, metastasis, invasion, and proliferation. In order to simulate the spatial confinement of the cells, a novel 3D platform consisted of a collagen hydrogel with heterogeneous sections of bundled collagen architectures. Meant to mimic the stratified dermis layers of skin. Patient-derived human acral melanoma single cells and tumor spheres were placed in the gels, and stress-induced experiments were performed in order to investigate the cells’ response.
Mechanical compression demonstrated that melanoma cells incurred DNA damage from the compressive stress only, leading to double-stranded DNA breaks. The interactions then caused the melanoma cells to adopt a more malignant, protrusive, and invasive phenotype. This became more pronounced with mechanical compression. Regarding the tumor spheroid, compression reduced invasion but increased proliferation of the cells on the tumor periphery. The stress became even more pronounced on the peripheral cells from the extracellular matrix, which increased the proliferation of peripheral tumor cells.
Treatment with inhibitors for actin polymerization and actin myosin contractility, which would cause the cell not to sense the mechanical stress from the environmental stimulus. The inhibitor partially rescued acral melanoma DNA damage and reduced cell protrusions and movement. Potential therapies against acral melanomas would target actin and myosin proteins, preventing the mechanical stress response that would otherwise drive DNA damage and increase mutation rates. Suggesting that actin and contractility inhibitors may mitigate malignancy upon compressive stress.
Work’s Cited:
Khan, Z.M., Rossello-Martinez, A., Mak, M. Impact of Mechanical and Architectural Signals in the Tumor Microenvironment on Melanoma, Advanced Healthcare Materials, (2025).
