Invasion by cancer cells is a crucial step in metastasis. An oversimplified view in the literature is that cancer cells become more deformable as they become more invasive. β-adrenergic receptor (βAR) signaling drives invasion and metastasis, but the effects on cell deformability are not known. Here, we show that activation of β-adrenergic signaling by βAR agonists reduces the deformability of highly metastatic human breast cancer cells, and that these stiffer cells are more invasive in vitro. We find that βAR activation also reduces the deformability of ovarian, prostate, melanoma and leukemia cells. Mechanistically, we show that βAR-mediated cell stiffening depends on the actin cytoskeleton and myosin II activity. These changes in cell deformability can be prevented by pharmacological β-blockade or genetic knockout of the β 2 -adrenergic receptor. Our results identify a β 2 -adrenergicCa 2+ -actin axis as a new regulator of cell deformability, and suggest that the relationship between cell mechanical properties and invasion might be dependent on context.

Immune cells can sense and respond to biophysical cues — from dynamic forces to spatial features — during their development, activation, differentiation and expansion. These biophysical signals regulate a variety of immune cell functions such as leukocyte extravasation, macrophage polarization, T cell selection and T cell activation. Recent studies have advanced our understanding on immune responses to biophysical cues and the underlying mechanisms of mechanotransduction, which provides rational basis for the design and development of immune-modulatory therapeutics. This review discusses the recent progress in mechanosensing and mechanotransduction of immune cells, particularly monocytes/macrophages and T lymphocytes, and features new biomaterial designs and biomedical devices that translate these findings into biomedical applications.

The physical properties of cells are promising biomarkers for cancer diagnosis and prognosis. Here we determine the physical phenotypes that best distinguish human cancer cell lines, and their relationship to cell invasion. We use the high throughput, single-cell microfluidic method, quantitative deformability cytometry (q-DC), to measure six physical phenotypes including elastic modulus, cell fluidity, transit time, entry time, cell size, and maximum strain at rates of 102 cells per second. By training a k-nearest neighbor machine learning algorithm, we demonstrate that multiparameter analysis of physical phenotypes enhances the accuracy of classifying cancer cell lines compared to single parameters alone. We also discover a set of four physical phenotypes that predict invasion; using these four parameters, we generate the physical phenotype model of invasion by training a multiple linear regression model with experimental data from a set of human ovarian cancer cells that overexpress a panel of tumor suppressor microRNAs. We validate the model by predicting invasion based on measured physical phenotypes of breast and ovarian human cancer cell lines that are subject to genetic or pharmacologic perturbations. Taken together, our results highlight how physical phenotypes of single cells provide a biomarker to predict the invasion of cancer cells.

The ability of cells to deform and generate forces are key mechanical properties that are implicated in metastasis. While various soluble and mechanical cues are known to regulate cancer cell mechanical phenotype or mechanotype, our knowledge of how cells translate external signals into changes in mechanotype is still emerging. We previously discovered that activation of β -adrenergic signaling, which results from soluble stress hormone cues, causes cancer cells to be stiffer or less deformable; this stiffer mechanotype was associated with increased cell motility and invasion. Here, we characterize how β -adrenergic activation is translated into changes in cellular mechanotype by identifying molecular mediators that regulate key components of mechanotype including cellular deformability, traction forces, and nonmuscle myosin II (NMII) activity. Using a micropillar assay and computational modelling, we determine that β AR activation increases cellular force generation by increasing the number of actin-myosin binding events; this mechanism is distinct from how cells increase force production in response to matrix stiffness, suggesting that cells regulate their mechanotype using a complementary mechanism in response to stress hormone cues. To identify the molecules that modulate cellular mechanotype with β AR activation, we use a high throughput filtration platform to screen the effects of pharmacologic and genetic perturbations on β AR regulation of whole cell deformability. Our results indicate that β AR activation decreases cancer cell deformability and increases invasion by signaling through RhoA, ROCK, and NMII. Our findings establish β AR-RhoA-ROCK-NMII as a primary signaling axis that mediates cancer cell mechanotype, which provides a foundation for future interventions to stop metastasis.