Mechanical confinement governs phenotypic plasticity in melanoma

Area of Science:

• Cellular plasticity and cancer biology
• Mechanobiology and epigenetics

Background:

• Phenotype switching allows cancer cells to alternate between proliferative and invasive states.
• The external cues triggering this cellular plasticity remain largely unidentified.

Purpose of the Study:

• To investigate the role of mechanical confinement in mediating cancer cell phenotype switching.
• To identify the molecular mechanisms underlying confinement-induced phenotype changes.

Main Methods:

• Utilized a zebrafish melanoma model and human samples.
• Employed spatial and single-cell transcriptomics to profile tumor cells.
• Conducted morphological analysis and quantitative modeling.

Main Results:

• Mechanical confinement induces chromatin remodeling, leading to phenotype switching.
• Identified HMGB2 as a key mediator, upregulated in confined cells.
• Confined HMGB2-high melanoma cells exhibit reduced proliferation and increased drug resistance.

Conclusions:

• The mechanical microenvironment is a critical driver of melanoma phenotype switching.
• HMGB2 mediates the trade-off between proliferative and invasive states.
• Targeting mechanical cues or HMGB2 may offer new therapeutic strategies.