Abstract: High extracellular matrix stiffness is a prominent feature of malignant tumors associated with poor clinical prognosis. Previous studies have shown that increased matrix stiffness promotes cancer metastasis and invasion, and contributes to reduced drug penetration, thus substantially decreasing chemotherapeutic effect. One potential treatment for breast cancer under active clinical investigation is through attenuating the enhanced local ECM stiffness. To elucidate the mechanistic connections between increased matrix stiffness and tumor progression, a variety of hydrogel scaffolds with dynamic changes in stiffness have been developed. These approaches which usually make use of high temperature, strong irradiation, and acidic/basic pH, are not biocompatible, often lack reversibility (can only stiffen and not soften) and does not allow study on the same cell population longitudinally.
Description: In this work, we describe a hydrogel platform capable of magneto-stiffening/softening to study the effects of dynamically changing matrix stiffness on 3D cancer spheroids. Harnessing static external magnetic field, the mechanical stiffness of hydrogel platform is tuneable between 500 and 2700 Pa, mimicking healthy and malignant breast tissues, respectively. Taking advantages of magnetic modulation and mechano-elastic profile of our material, the matrix stiffness of hydrogel can be reversibly changed by manipulating magnetic strength, and this stiffening/softening process can be repeated multiple times without affecting the properties of the material.
With this platform, as expected, we found that matrix stiffness increased tumor malignancy including epithelial-to-mesenchymal transition and hypoxia, while reduced drug sensitivity and tumor-killing effects. More interestingly, these malignant transformations can be halted or reversed with matrix softening (i.e., mechanical rescue) which down-regulatedkey cell activators including YAP1 and NRF2. We also found, in agreement with published literature that matrix stiffening reduced cancer killing effect of doxorubicin while matrix softening process could reverse chemoresistance and potentiate drug efficacy. These findings demonstrate the of reducing local matrix stiffness to increase drug efficacy and improve cancer treatment.
Conclusions: We propose that our platform can be used to deepen understanding of the impact of matrix softening on cancer biology – an important but rarely studied phenomenon. In the future, with patient-derived cancer cells and primary clinical data, it will be a powerful tool for applications such as mechanical rescue of cellular states and drug screening, and to create clinical impact.
