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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Mechanical confinement governs phenotypic plasticity in melanoma.

Miranda V Hunter1, Eshita Joshi2, Sydney Bowker3

  • 1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. hunterm@mskcc.org.

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Summary

Mechanical confinement drives cancer cell phenotype switching via chromatin remodeling. This process involves the HMGB2 protein, influencing cell states and drug resistance in melanoma.

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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.