Robust gene expression programs underlie recurrent cell states and phenotype switching in melanoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Melanoma cells can transition between distinct cellular states, including melanocytic and mesenchymal-like phenotypes.
• Evidence suggests the existence of intermediate states, but their nature and regulatory mechanisms remain unclear.

Purpose of the Study:

• To identify and characterize intermediate states in melanoma.
• To decipher the gene regulatory network (GRN) governing these states and phenotype switching.

Main Methods:

• Single-cell and bulk RNA sequencing (RNA-seq) of melanoma cultures.
• Chromatin landscape analysis.
• Single-cell migration assays.
• Gene knockdown experiments (SOX10) with time-series sampling.

Main Results:

• Identified shared GRNs for melanocytic, mesenchymal, and a novel intermediate state.
• Characterized the intermediate state by its distinct chromatin landscape and migratory phenotype.
• Identified key transcription factors (SOX6, NFATC2, EGR3, ELF1, ETV4) governing the intermediate state.
• Unraveled the sequential GRN arrangements during phenotype switching after SOX10 knockdown.

Conclusions:

• An intermediate melanoma cell state exists, characterized by a unique GRN.
• This intermediate state is stable and driven by a 'mixed' GRN, not a heterogeneous mix of cells.
• The findings provide insights into melanoma plasticity and potential therapeutic targets.