Matrix Stiffness-Encoded Mechanical Memory Maintains Proliferative Dominance in Metastatic Tumors

Area of Science:

• Oncology
• Cell Biology
• Biophysics

Background:

• Primary and metastatic tumors exhibit similar biological characteristics despite differing microenvironments.
• Understanding how tumor cells maintain phenotypic consistency in varied microenvironments is crucial for developing anti-metastasis strategies.

Purpose of the Study:

• To investigate the role of mechanical memory in sustaining tumor cell malignancy under biomechanical stress.
• To elucidate the molecular mechanisms linking matrix stiffness, epigenetic reprogramming, and metastasis.

Main Methods:

• Analysis of the RhoA-ROCK1 signaling pathway activation in response to matrix stiffness.
• Assessment of mitochondrial dynamics, including fission and fatty acid oxidation.
• Evaluation of epigenetic modifications (histone acetylation) and their mitotic heritability.
• Inhibition of RhoA-ROCK1 to assess its effect on mechanical memory and metastasis.

Main Results:

• Mechanical memory allows tumor cells to withstand biomechanical stress and maintain malignant traits.
• Matrix stiffness activates RhoA-ROCK1, suppressing mitochondrial fission and enhancing fatty acid oxidation.
• This leads to acetyl-CoA accumulation, histone hyperacetylation, and mitotically heritable epigenetic reprogramming.
• Inhibiting RhoA-ROCK1 successfully disrupted mechanical memory and reduced metastasis.

Conclusions:

• Mechanical memory is a key mechanism by which tumor cells adapt to and sustain malignancy in diverse microenvironments.
• The RhoA-ROCK1 pathway and subsequent epigenetic changes are critical mediators of stiffness-induced mechanical memory.
• Targeting mechanical memory, specifically by inhibiting RhoA-ROCK1, presents a promising therapeutic strategy for preventing cancer metastasis.