Morphodynamics facilitate cancer cells to navigate 3D extracellular matrix

Area of Science:

• Cell biology
• Biophysics
• Cancer research

Background:

• Cell shape is intrinsically linked to cell function, yet the significance of cell morphodynamics (temporal shape fluctuations) remains underexplored.
• Understanding cell morphodynamics in 3D environments is crucial for deciphering complex biological processes like cancer cell migration.

Purpose of the Study:

• To investigate the morphodynamics of MDA-MB-231 breast cancer cells migrating within type I collagen extracellular matrix (ECM).
• To determine how external factors (ECM mechanics) and internal factors (Rho/ROCK-signaling) influence cancer cell morphodynamics and migration modes.
• To establish a framework for predicting and controlling 3D cancer cell motility through understanding morphodynamics.

Main Methods:

• Systematic variation of ECM physical properties by adjusting collagen concentration, alignment, and gelation temperatures.
• Application of machine learning algorithms to classify cell shapes into four distinct morphological phenotypes, each associated with a specific migration mode.
• Characterization of mesoscale dynamics, including phenotype occurrence probability, dwell time, and transition matrices under varying ECM conditions.

Main Results:

• 3D migrating cancer cell morphodynamics are externally controlled by ECM mechanics and internally modulated by Rho/ROCK-signaling.
• Machine learning successfully classified cell shapes into phenotypes corresponding to distinct migration modes, enabling mapping of morphodynamics to phenotype evolution.
• Cancer cell motility in 3D was modeled as a hidden Markov process, demonstrating coupling between cell migration step size and simultaneous cell morphodynamics.
• Phenotype transitions were shown to facilitate cancer cell navigation through non-uniform ECM, including traversing interfaces between different microstructures.

Conclusions:

• 3D migrating cancer cells display complex morphodynamics regulated by ECM mechanics and Rho/ROCK-signaling, which in turn govern cell motility.
• The study establishes a link between cell morphodynamics, ECM properties, and cancer cell migration, offering insights into cancer progression.
• These findings provide a foundation for the mechanical programming of cell morphodynamics to predict and control 3D cancer cell motility.