Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

Abstract

The persistence of drug resistant cell populations following chemotherapeutic treatment is a significant challenge in the clinical management of cancer. Resistant subpopulations arise via both cell intrinsic and extrinsic mechanisms. Extrinsic factors in the microenvironment, including neighboring cells, glycosaminoglycans, and fibrous proteins impact therapy response. Elevated levels of extracellular fibrous proteins are associated with tumor progression and cause the surrounding tissue to stiffen through changes in structure and composition of the extracellular matrix (ECM). We sought to determine how this progressively stiffening microenvironment affects the sensitivity of breast cancer cells to chemotherapeutic treatment. MDA-MB-231 triple negative breast carcinoma cells cultured in a 3D alginate-based hydrogel system displayed a stiffness-dependent response to the chemotherapeutic doxorubicin. MCF7 breast carcinoma cells cultured in the same conditions did not exhibit this stiffness-dependent resistance to the drug. This differential therapeutic response was coordinated with nuclear translocation of YAP, a marker of mesenchymal differentiation. The stiffness-dependent response was lost when cells were transferred from 3D to monolayer cultures, suggesting that endpoint ECM conditions largely govern the response to doxorubicin. To further examine this response, we utilized a platform capable of dynamic ECM stiffness modulation to allow for a change in matrix stiffness over time. We found that MDA-MB-231 cells have a stiffness-dependent resistance to doxorubicin and that duration of exposure to ECM stiffness is sufficient to modulate this response. These results indicate the need for additional tools to integrate mechanical stiffness with therapeutic response and inform decisions for more effective use of chemotherapeutics in the clinic.

Concepts of extracellular matrix remodelling in tumour progression and metastasis

“…Novel technologies like multiplexed ion beam imaging (MIBI) can provide a quantitative map of the Box 2 | Therapies targeting ECM remodelling in cancer and metastasis ECM stiffness increases cancer cell proliferation and survival, and induces immunosuppression, even during therapy 286 . Tumourigenic ECM modifications and stiffness can also influence responses to anticancer agents in vitro 287 . Therapies that resolve such stiffness may allow for improved drug penetration to the tumour cells.…”

Anticancer Immunotherapy by MFAP5 Blockade Inhibits Fibrosis and Enhances Chemosensitivity in Ovarian and Pancreatic Cancer

“…This is the first report demonstrating that MFAP5 blockade reduced fibrosis in both ovarian and pancreatic cancers through down-regulation of fibrosis-related genes including COL1A1 and COL11A1. Fibrosis in tumor tissue has been shown to increase tissue matrix stiffness, which promotes tumor progression and confers chemoresistance (32)(33)(34). Fibrosis-related genes such as COL11A1 has been shown to confer cisplatin resistance in ovarian cancer cells (35).…”

A three-dimensional bioprinted model to evaluate the effect of stiffness on neuroblastoma cell cluster dynamics and behavior

“…The stiffness properties of the printed hydrogels without bioinks, determined by Young's modulus as previously described, increased in line with AlgMA concentrations 43 , and no significant differences were found comparing the Young's modulus values of each stiffness at 37 °C or at room temperature, which confirms that all measurements carried out in human tumors, mice tumors and hydrogels are comparable at room temperature. However, the Young's modulus decrease in composite hydrogels bioprinted and incubated with SK-N-BE(2) for 24 days with 1% and 2% AlgMA indicates an increased elasticity in these hydrogels 53 . Among other factors, this could be linked to cell-mediated hydrogel degradation as cells grow, releasing matrix metalloproteinases (MMP) 54 , but also to cell proliferation and migration through the hydrogel, and the softer consistency of the tumor cells compared to the ECM 55,56 .…”