Effects of Intracellular Force Localization on Cancer Cell Invasion: Revealing Mechanical Trade-offs through...

Area of Science:

• Biophysics
• Cancer Biology
• Cell Mechanics

Background:

• Metastasis drives most cancer deaths, involving cancer cell forces on their microenvironment.
• Actin is key for cell force and motility, but intracellular force localization's role in invasion is understudied.
• Previous work established a clinically relevant assay and finite element models for cancer cell invasion.

Purpose of the Study:

• To investigate how intracellular force application location (top vs. bottom of nucleus) impacts cancer cell invasion efficiency.
• To analyze the effects of force localization on indentation depth, intracellular stress, and force transmission to the microenvironment.
• To understand the mechanical trade-offs between invasion and cellular stability based on force application.

Main Methods:

• Utilized experimentally validated finite element models of cancer cell invasion.
• Simulated force application at the top and bottom of the nucleus under varying force levels (≤100 nN and ≥150 nN).
• Analyzed indentation depths, intracellular stress, nuclear stress, and stress transmitted to the surrounding gel.

Main Results:

• Low forces (≤100 nN): Top forces caused deeper indentations (35-42%) but less gel stress (~10%).
• High forces (≥150 nN): Bottom forces transmitted >15% more gel stress, with comparable indentation depths and significantly reduced nuclear stress (>250%).
• These effects were more pronounced when cytoplasm was softer than the nucleus, typical for invasive cancer cells.

Conclusions:

• Intracellular force localization critically influences invasion efficiency and cellular stability.
• Top-applied forces may favor shallow invasion in soft environments.
• Bottom-applied forces, mimicking leading-edge protrusions, optimize deep invasion with reduced risk to cell integrity, suggesting potential anti-metastatic targets.