Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution

Single-cell sequencing has revealed cell state heterogeneity across diverse healthy and malignant tissues. However, the extent these cell states are plastic or heritable remains largely unknown. To address this, we introduce PATH (Phylogenetic Analysis of Trait Heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Here, we used PATH to measure phylogenetic correlations on single-cell phylogenies derived from gliomaspheres to reveal the somatic evolutionary relationships between Neural Progenitor-like (NPC), Oligodendrocyte Progenitor-like (OPC), Astrocyte-like (AC), and Mesenchymal-like (MES) cancer cell states. Overall design: Single-cell RNA sequencing and lineage tracing using molecular recording in gliomasphere.