Differentiation-related epigenomic changes define clinically distinct keratinocyte cancer subclasses

Area of Science:

• Dermatology and Cancer Biology
• Epigenetics and Single-Cell Genomics

Background:

• Keratinocyte cancers (KC), including basal cell carcinoma and cutaneous squamous cell carcinoma, are common skin malignancies.
• Understanding the cellular origins and epigenomic landscape of KC is crucial for improving patient outcomes.

Purpose of the Study:

• To investigate the epigenomic dynamics during human epidermal differentiation using single-cell multi-omics.
• To identify distinct subtypes of KC based on DNA methylation and their cellular origins.
• To link KC subtypes and their cellular origins to clinical features and prognosis.

Main Methods:

• Combined single-cell transcriptomics and methylomics to analyze epidermal differentiation.
• Identified differentially accessible regulatory regions in keratinocytes.
• Utilized cell-type deconvolution and methylome integration to determine KC subclasses and cells-of-origin.

Main Results:

• Identified ~3,800 differentially accessible regions linked to key transcription factors during keratinocyte differentiation.
• DNA methylation patterns defined KC subtypes with stem cell-like or differentiated keratinocyte-like features.
• Linked invasive and metastatic KC cases to undifferentiated cells-of-origin, revealing distinct clinical features.

Conclusions:

• Characterized the epigenomic dynamics of human keratinocyte differentiation.
• Established novel links between KC cells-of-origin, epigenomic subtypes, and patient prognosis.
• Provides a foundation for understanding KC heterogeneity and developing targeted therapies.