Cell Cytoskeleton and Stiffness Are Mechanical Indicators of Organotropism in Breast Cancer

SIMPLE SUMMARY: Cancer cell dissemination exhibits organ preference or organotropism. Although the influence of intrinsic biochemical factors on organotropism has been intensely studied, little is known about the roles of mechanical properties of metastatic cancer cells. Our study suggests that there may be a correlation between cell cytoskeleton/stiffness and organotropism. We find that the cytoskeleton and stiffness of breast cancer cell subpopulations with different metastatic preference match the mechanics of the metastasized organs. The modification of cell cytoskeleton significantly influences the organotropism-related gene expression pattern and mechanoresponses on soft substrates which mimic brain tissue stiffness. These findings highlight the key role of cell cytoskeleton in specific organ metastasis, which may not only reflect but also impact the metastatic organ preference. ABSTRACT: Tumor metastasis involves the dissemination of tumor cells from the primary lesion to other organs and the subsequent formation of secondary tumors, which leads to the majority of cancer-related deaths. Clinical findings show that cancer cell dissemination is not random but exhibits organ preference or organotropism. While intrinsic biochemical factors of cancer cells have been extensively studied in organotropism, much less is known about the role of cell cytoskeleton and mechanics. Herein, we demonstrate that cell cytoskeleton and mechanics are correlated with organotropism. The result of cell stiffness measurements shows that breast cancer cells with bone tropism are much stiffer with enhanced F-actin, while tumor cells with brain tropism are softer with lower F-actin than their parental cells. The difference in cellular stiffness matches the difference in the rigidity of their metastasized organs. Further, disrupting the cytoskeleton of breast cancer cells with bone tropism not only elevates the expressions of brain metastasis-related genes but also increases cell spreading and proliferation on soft substrates mimicking the stiffness of brain tissue. Stabilizing the cytoskeleton of cancer cells with brain tropism upregulates bone metastasis-related genes while reduces the mechanoadaptation ability on soft substrates. Taken together, these findings demonstrate that cell cytoskeleton and biophysical properties of breast cancer subpopulations correlate with their metastatic preference in terms of gene expression pattern and mechanoadaptation ability, implying the potential role of cell cytoskeleton in organotropism.