Gradient and Dynamic Hydrogel Materials to Probe Dynamics in Cancer Stem Cell Phenotypes

Abstract

The microenvironment of tumors shows high variability in stiffness compared to normal tissues, suggesting that spatiotemporal changes in mechanics play a role in development and progression. Here, we employ microengineered hydrogels with static, dynamic (magnetic field-mediated stiffening and softening), or gradient matrix elasticity to investigate the influence of matrix mechanics in modulating the stem cell-like phenotype in melanoma and breast cancer cells. Using immunofluorescence staining of molecular markers associated with a cancer stem cell (CSC) state, we show that a subtle increase in local stiffness promotes the CSC phenotype, while different mechanical properties in static or dynamic hydrogels—without gradient profiles of mechanical properties—have a negligible influence on phenotype switching toward a CSC state. Inhibition of integrins and downstream effectors of mechanotransduction reveals that distinct signaling pathways play a role in regulating the dynamic CSC state in melanoma and breast cancer cells. Our findings demonstrate how cancer cells respond to the local stiffness gradients with dynamic plasticity during progression.