β-adrenergic signaling modulates cancer cell mechanotype through a RhoA-ROCK-myosin II axis

Abstract

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.

A spatial model of YAP/TAZ signaling reveals how stiffness, dimensionality, and shape contribute to emergent outcomes

“…We note that our model, even though validated against data from the literature, is limited to certain components of the A spatial model of YAP/TAZ signaling reveals how stiffness, dimensionality, and shape contribute to emergent outcomes signaling pathway and that integration of other biochemical pathways will be important to build on this present work (79)(80)(81)(82)(83).…”

Chemo-Mechanical Factors That Limit Cellular Force Generation

“…These factors are in-turn governed by intra-cellular and extra-cellular chemical and mechanical signals such as hypoxia, adrenergic signaling, growth factor signaling, substrate viscoelasticity and so on. [82,101,102]. In this work, we focused on the immediate regulators of cell traction force generation-myosin motor activity (primarily non-muscle myosin 2 interactions with actin filaments), actin- myosin filament coupling to cell-substrate adhesions, and substrate elastic response.…”

Transfer function for YAP/TAZ nuclear translocation revealed through spatial systems modeling

“…We note that our model, even though validated against data from the literature, is limited to certain components of the signaling pathway and that integration of other biochemical pathways will be important to build on this present work (76)(77)(78)(79)(80) . For example, here we have only discussed the interaction between the ECM and single cells, yet cell-cell interactions are very important in vivo and may be responsible for some of the changes observed between 2D and 3D systems in vitro (81,82) .…”