Epigenetic conservation infers that colorectal cancer progenitors retain the phenotypic plasticity of normal colon

Plasticity, or the ability to rapidly and reversibly change phenotypes, may help explain how a single progenitor cell eventually generates a tumor with many different cell phenotypes. Normal colon plasticity is characterized by a conserved and broadly permissive epigenome, where expression and phenotype are determined by the microenvironment instead of epigenetic remodeling. To determine whether this stem-like plasticity is retained during progression, gene expression was measured with spatial transcriptomics and compared with gene-level DNA methylation in two colorectal cancers (CRCs). Like normal colon, genes that were differentially expressed between regions, subclones, and phenotypes (superficial, invasive, and metastatic) tended to have lower DNA methylation variability. We propose a quantitative signal of plasticity that correlates gene epigenetic variability with gene expression variability. In this framework, negative correlation implies phenotypic plasticity, as more variably expressed genes tend to have less epigenetic variability. We verify the presence of this signal in multiple external single-cell RNA-Seq datasets, in both normal colon and CRC samples. Therefore, the plasticity of normal colon appears to be retained during progression. A CRC progenitor with a preconfigured plastic phenotype is poised for rapid growth because it expresses, as needed, transcripts required for progression with minimal epigenetic remodeling.