Mechanical forces within the tumor microenvironment are increasingly recognized as important regulators of cancer progression, yet their influence on apoptotic regulation in melanoma remains insufficiently defined. Here, we developed a customized stretchable culture platform capable of delivering physiologically relevant cyclic mechanical strain and investigated its effects on intrinsic apoptosis in melanoma cells with different metastatic potentials. Cyclic stretch significantly reduced apoptosis in high metastatic melanoma cells, while low-metastatic counterparts exhibited minimal or differential responses. Mechanistically, mechanical stimulation suppressed intrinsic mitochondrial apoptotic signaling along the BAD–BCL-2 family–BAX axis, leading to reduced caspase-3/7 activation. Pharmacological modulation of mechanosensitive channel activity and intracellular Ca 2+ signaling partially restored apoptotic responses under stretch, supporting the involvement of calcium-associated mechanotransduction in this process. Importantly, stretched high metastatic melanoma cells displayed reduced sensitivity to pharmacological apoptosis induction, indicating altered apoptotic responsiveness under mechanical stimulation. In vivo models further demonstrated that prior mechanical conditioning enhanced survival and metastatic behavior in high metastatic melanoma. Together, these findings reveal that cyclic mechanical stress promotes apoptosis resistance in a metastatic potential–dependent manner and highlight the importance of considering tissue mechanics in understanding melanoma progression and therapeutic response. • A custom-engineered cyclic stretching platform reveals that mechanical stress suppresses intrinsic apoptosis in highly metastatic melanoma cells. • Pharmacological inhibition experiments indicate that mechanosensitive channel–associated Ca 2+ signaling contributes to stretch-dependent apoptotic regulation. • Cross-species validation using mouse (B16F1/F10) and human (A375P/SM) melanoma models demonstrates conserved mechanoadaptive responses to cyclic mechanical stimulation. • In vivo tumor models reveal that melanoma cells mechanically preconditioned in vitro exhibit enhanced tumor growth and metastatic colonization, highlighting the potential role of mechanical environments in melanoma progression.
Lee et al. (Wed,) studied this question.