A mathematical model coupling polarity signaling to cell adhesion explains diverse cell migration patterns

Area of Science:

• Cell biology
• Biophysics
• Systems biology

Background:

• Cell migration relies on dynamic lamellipodia protrusion and retraction.
• Lamellipodial dynamics influence cell-extracellular matrix (ECM) interactions and signaling.
• Melanoma cell migration on fibronectin-coated substrates exhibits diverse lamellipodial behaviors.

Purpose of the Study:

• To investigate the interplay between intracellular and ECM signaling in regulating lamellipodial dynamics.
• To develop and test computational models explaining observed cell migration behaviors.
• To identify key molecular factors governing cell shape dynamics during migration.

Main Methods:

• Mathematical modeling of intracellular Rac-Rho signaling pathways.
• Coupling of intracellular signaling models with ECM signaling feedback mechanisms.
• Testing model predictions against experimental data from melanoma cell lines on topographic substrates.

Main Results:

• Identified models where Rac-GTPase drives protrusion and Rho-GTPase drives contraction.
• Demonstrated that ECM signaling modulates RhoA activity, influencing contraction.
• Showed that lamellipodial dynamics feed back to alter cell-ECM contact area and signaling levels.

Conclusions:

• Shared pools of Rac and Rho are critical for regulating competing lamellipodia.
• ECM signaling directly activates RhoA, impacting cell contractility.
• Feedback between lamellipodial dynamics and ECM signaling generates diverse cell migration behaviors.