Mechanobiology: how mechanics regulate life

Selected Questions:

1. The article explains that fibronectin scaffolds allow force transmission between CAFs, but how do these structures physically connect the cells and coordinate their actions? In other words, how do the extracellular matrix and fibronectin fibres contribute to the force transmission between CAFs and cancer cells?

2. What is the mechanism behind the formation of the capsule around the tumor?

3. It is stated that “the observation of inward-pointing traction forces underneath the cancer cells suggests that the CAFs generate shear stress on the cell”. Why is it shear stress and not traction/compression (as it is pointing toward the cell)? Additionally, the stress is modeled as viscous friction, what suggests that this model is an accurate representation of the phenomenon? The article mentioned that shear stress drives inward flow of cancer cells and cluster deformation, also “average tangential force,…, remained low and constant over time”. Why do the cancer cells flow inwards and why does the average tangential force remain constant over time? 

4. What is the purse-string mechanism? Why do you think the multicellular ring formed by CAFs stopped advancing after 8 hours, and what might be the significance of this timing in relation to the formation and stabilization of the bud?

5. So CAFs compartmentalize and compress cancer cells. I'm assuming they compartmentalize to get smaller buds, which, by virtue of being smaller, are more stably maintained. This idea wasn't really explored however. The in vitro evolution of CAF rings may not accurately represent the full 3D picture. How feasible would it be to make a 3D experiment in which different diameter spheres of CAFs encapsulating cancer cells are studied and perturbed to assess stability?

6. Do cancer cells exhibit any resistance to CAF compression? If I understand correctly, cancer cells tend to wait until the compressive wall is broken before spreading more aggressively.

7. How could the squeezing of cancer cells by CAFs both slow down tumor growth and at the same time help the cancer become more aggressive, like resisting treatment or spreading?

8. In Figure 4d it seems that the forces on the CAFs ring are almost twice as high in some regions than in others. In the upper row, the forces in the top right are of around 400 Pa whereas on the lower left they are around 200-250 Pa. How do you explain that we don't observe unilateral shrinking or uniform displacement?

9. Is there a synergistic effect between contractility and proliferative behavior of CAF to co-regulate the pressure exerted on cancer cells? When the proliferative behavior of CAF is weakened, can the contractility of CAF be automatically enhanced to compensate for the reduction in the amount of CAF and thus maintain the pressure on the tumor?

10. What is the significance of YAP translocation into the nucleus? Please explain the mechanism behind the YAP nuclear transport.