Beyond matrix stiffness: targeting force-induced cancer drug resistance

Area of Science:

• Oncology
• Biophysics
• Cell Biology

Background:

• Tumor progression involves mechanical abnormalities within the tumor microenvironment (TME).
• These mechanical cues activate cellular signaling pathways, influencing tumor growth and therapeutic resistance.
• Key mechanical factors include extracellular matrix (ECM) composition/stiffness, interstitial fluid pressure (IFP), and mechanical forces.

Purpose of the Study:

• To review mechanisms of anti-cancer therapies and mechanotransduction in the context of TME mechanical abnormalities.
• To elucidate how TME mechanical factors impact therapeutic response and drug resistance.
• To discuss current and future strategies targeting mechanical pathways in cancer treatment.

Main Methods:

• Literature review of anti-cancer therapies and mechanotransduction pathways.
• Analysis of the impact of mechanical TME abnormalities on cellular processes (proliferation, apoptosis, survival, phenotype switching).
• Review of drugs targeting TME mechanical properties or mechanosensors.

Main Results:

• Mechanical TME abnormalities significantly influence cellular programs and therapeutic outcomes.
• High ECM stiffness, IFP, and mechanical forces contribute to tumor growth and drug resistance.
• Drugs normalizing TME mechanics or blocking mechanotransduction pathways show therapeutic potential.

Conclusions:

• Understanding and targeting mechanical TME abnormalities is crucial for overcoming drug resistance.
• Developing novel strategies that address mechanotransduction pathways presents a promising avenue for cancer therapy.
• Further research is needed to translate these findings into effective clinical applications.