Cell stiffness and TBX3 expression have been identified as biomarkers of melanoma metastasis in 2D environments. This study aimed to determine how mechanical and biochemical properties of melanoma cells change during cluster formation and metastasis in 3D environments mimicking physiological conditions. In isolated cells, mitochondrial fluctuations decreased, and stiffness increased across disease stages and matrix rigidities. TBX3 was overexpressed in soft but diminished in stiff matrices. During cluster formation in soft matrices, the intracellular properties of VGP cells did not change during extensive cluster formation, whereas mitochondrial fluctuations increased and TBX3 expression decreased in MET cells during limited cluster formation. In stiff matrices, cluster formation was restricted, mitochondrial fluctuations and TBX3 expression increased in VGP and MET, and cell stiffness increased in VGP and decreased in MET. Mitochondrial activity, cell stiffness, and TBX3 expression jointly affected cluster formation and metastasis in melanoma, with contributions varying with environmental properties. Hence, biomechanical and biochemical properties of the cells and the environment should be combined to advance targeted cancer therapies.
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