Biomechanical regulation of drug sensitivity in an engineered model of human tumor

Abstract

Predictive testing of anticancer drugs remains a challenge. Bioengineered systems, designed to mimic key aspects of the human tumor microenvironment, are now improving our understanding of cancer biology and facilitating clinical translation. We show that mechanical signals have major effects on cancer drug sensitivity, using a bioengineered model of human bone sarcoma. Ewing sarcoma (ES) cells were studied within a three-dimensional (3D) matrix in a bioreactor providing mechanical loadings. Mimicking bone-like mechanical signals within the 3D model, we rescued the ERK1/2-RUNX2 signaling pathways leading to drug resistance. By culturing patient-derived tumor cells in the model, we confirmed the effects of mechanical signals on cancer cell survival and drug sensitivity. Analyzing human microarray datasets, we showed that RUNX2 expression is linked to poor survival in ES patients. Mechanical loadings that activated signal transduction pathways promoted drug resistance, stressing the importance of introducing mechanobiological cues into preclinical tumor models for drug screening.

Perfusion applied to a 3D model of bone metastasis results in uniformly dispersed mechanical stimuli

“…Compression‐induced fluid flow reduced breast cancer cell gene expression of Runx2, a transcription factor that is required to induce osteolysis in bone metastatic breast cancer (Barnes et al, ; Lynch et al, ). In contrast, compression‐induced fluid flow upregulated Runx2 expression in osteosarcoma cells, leading to enhanced survival and chemotherapy resistance (Marturano‐Kruik et al, ; Sadikovic et al, ). The computed stimuli in the osteosarcoma study (max velocity ∼4.0 µm/s, max pressure ∼1.4 kPa), however, were much lower than our values.…”

“…Moreover, the relative contributions of matrix deformation and interstitial fluid flow, stimuli inherent to the skeleton mechanical environment, also require examination. In the current study, we focused on interstitial fluid flow, accomplished by applying perfusion in vitro, due to its well‐documented role in breast cancer metastasis and in stimulating bone anabolism (Fritton & Weinbaum, ), but matrix strain likely also plays a role (Lynch et al, ; Marturano‐Kruik et al, ; Pagnotti et al, ).…”

On the biomechanical properties of osteosarcoma cells and their environment

“…Additionally, osteosarcoma cell malignancy correlates with reduced focal adhesion (FA) count, smaller contractility potential and softening of the cell cortex. compressive mechanical loading on Ewing's sarcoma, the second form of bone cancer in terms of incidence (Marturano-Kruik et al, 2015;Marturano-Kruik et al, 2018). Their results reveal that under physiological load regimes Ewing's sarcoma cells rescue signaling pathways, including Erk1/2-Runx2 signaling, that promote tumor development and proliferation and confer chemoresistance to the cells.…”

Development of a soft cell confiner to decipher the impact of mechanical stimuli on cells

“…We anticipate that this device could be a valuable tool for the fundamental understanding of the effect of cell confinement on various hallmarks of cancer progression and resistance, and in particular to decipher the role of nuclear mechanosensitivity. Links between cell resistance to treatment and mechanical stimuli have been highlighted recently [49,67,68]. Such mechanical cues could hence lead to new therapeutic approaches [69] that could be tested using such systems.…”