Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling

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. beta-adrenergic receptor (beta AR) signaling drives invasion and metastasis, but the effects on cell deformability are not known. Here, we show that activation of beta-adrenergic signaling by beta AR agonists reduces the deformability of highly metastatic human breast cancer cells, and that these stiffer cells are more invasive in vitro. We find that beta AR activation also reduces the deformability of ovarian, prostate, melanoma and leukemia cells. Mechanistically, we show that beta AR-mediated cell stiffening depends on the actin cytoskeleton and myosin II activity. These changes in cell deformability can be prevented by pharmacological beta-blockade or genetic knockout of the beta 2-adrenergic receptor. Our results identify a beta(2)-adrenergic-Ca2+- 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.