The findings from this study on caveolae-mediated mechanotransduction in 2D migrating cells provide valuable insights that can be extrapolated to 3D migration in complex tissue environments. In both 2D and 3D migration, the rear of migrating cells exhibits a front-rear gradient in membrane tension, with caveolae playing a critical role in sensing and responding to these mechanical cues. The dynamic caveolae-associated protein network identified in this study, enriched in cortical actin regulators and focal adhesion proteins, is highly sensitive to changes in membrane tension.
In complex tissue environments, such as during development or in pathological conditions like cancer metastasis, cells encounter diverse mechanical cues that influence their migration behavior. The regulation of caveolae assembly/disassembly, actomyosin contractility, and cell rear retraction by membrane tension and the associated protein network is likely to be crucial for efficient 3D migration. The spatio-temporal coordination of caveolae with the actin cytoskeleton and signaling molecules like ROCK and ARHGAP29 may play a significant role in guiding cell migration through complex tissue environments. Understanding the mechanisms of caveolae-mediated mechanotransduction in 2D migrating cells can provide a framework for studying and manipulating cell migration in 3D contexts.