Ultrasound‐Induced Mechanical Compaction in Acoustically Responsive Scaffolds Promotes Spatiotemporally Modulated Signaling in Triple Negative Breast Cancer

Abstract

Cancer cells continually sense and respond to mechanical cues from the extracellular matrix (ECM). Interaction with the ECM can alter intracellular signaling cascades, leading to changes in processes that promote cancer cell growth, migration, and survival. The present study used a recently developed composite hydrogel composed of a fibrin matrix and phase‐shift emulsion, termed an acoustically responsive scaffold (ARS), to investigate effects of local mechanical properties on breast cancer cell signaling. Treatment of ARSs with focused ultrasound drives acoustic droplet vaporization (ADV) in a spatiotemporally controlled manner, inducing local compaction and stiffening of the fibrin matrix adjacent to the matrix–bubble interface. Combining ARSs and live single cell imaging of triple‐negative breast cancer cells, it is discovered that both basal and growth‐factor stimulated activities of protein kinase B (also known as Akt) and extracellular signal‐regulated kinase (ERK), two major kinases driving cancer progression, negatively correlate with increasing distance from the ADV‐induced bubble both in vitro and in a mouse model. Together, these data demonstrate that local changes in ECM compaction regulate Akt and ERK signaling in breast cancer and support further applications of the novel ARS technology to analyze spatial and temporal effects of ECM mechanics on cell signaling and cancer biology.

Ultra-high-speed dynamics of acoustic droplet vaporization in soft biomaterials: Effects of viscoelasticity, frequency, and bulk boiling point

“…This led to strain buildup in the matrix during ADV. Since fibrin, like other natural biomaterials, exhibits strain stiffening behavior, ADV-generated bubbles can induce significant compaction and stiffening at the bubble-fibrin interface [66] , [67] . ADV-induced strain stiffening, evident by significantly brighter fluorescence intensities in confocal images ( Fig 3 , Fig 5 , Fig 7 ) post-ultrasound, was observed for all the three phase-shift droplets regardless of stable or transient bubble formation.…”

“…ADV-induced strain stiffening, evident by significantly brighter fluorescence intensities in confocal images ( Fig 3 , Fig 5 , Fig 7 ) post-ultrasound, was observed for all the three phase-shift droplets regardless of stable or transient bubble formation. This is important since ADV-induced stiffening in natural biomaterials can enable on-demand modulation (i.e., both spatially and temporally) of cellular phenotype and signaling [67] , [68] .…”

Stimuli-responsive hydrogel based on natural polymers for breast cancer

“…Thus, ultrasound waves induced local alteration in ECM compaction, which regulates breast cancer’s Akt and ERK signaling pathways. The novel ultrasound-responsive fibrin hydrogel technology could visualize ECM mechanics in cell signaling and breast cancer biology ( Humphries et al, 2022 ).…”

Bubble nucleation and dynamics in acoustic droplet vaporization: a review of concepts, applications, and new directions

“…Panels B, C, D, and G reprinted from Farrell, Aliabouzar [113] , with permission from Elsevier. Panels E and F reprinted from Humphries, Aliabouzar [114] with permission from John Wiley and Sons. …”

“…On-demand micromechanical changes induced via ADV can have broad biomedical applications and lead to novel approaches. Two recent studies used this approach for on-demand modulation of cellular signaling in a cancer model [114] ( Fig. 6 A) and cell differentiation [113] ( Fig.…”