Figure 7 from Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm

Heritability and plasticity of cellular phenotypes. A and B, We propose a conceptual model in which genetic mutations and CNAs, together with heritable chromatin accessibility profiles, determine the cellular memory of a certain clone (A), positioning it within a certain heritable fitness landscape (B). However, the clone does not manifest as a single transcriptional phenotype but rather as a set of transcriptional programs that could be represented within a Waddington landscape, similarly to those that regulate development (C). Darwinian selection acts at the phenotypic level, likely exerting selective pressure at the base of the Waddington landscape. This pressure may favor only a subset of a clone’s transcriptional programs, whereas the molecular memory encoding these programs may also retain other plastic phenotypes as a side effect. This may explain the persistent phenotypic heterogeneity and plasticity of cancer clones despite the strong selective pressure of treatments that, instead, should select for a single fittest phenotype. Created in BioRender. Sottoriva, A. (2025) https://BioRender.com/p3al29z.