Figure 6 from Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm

Inducing CIN before drug pressure. A and B, Single-cell copy-number profiles for the MSS AKT–mutant organoid untreated and after treatment with CENP-E and MPS1 inhibitors. This organoid seems to be stable and resilient to drug-induced alterations. C and D, Same as A and B but for the MSI organoid. In this case, the situation is different, and CENP-E and MPS1 inhibition causes a massive increase in instability, with a residual bulk of the population similar to the parental one. E and F, Bulk copy-number profile and population structure as recapitulated by barcode composition. Barcode composition matches copy-number clones, particularly evident with the blue trametinib-resistant barcode in the MSS AKT–mutant organoid. It is also clear how CENP-E inhibition induces significant changes in the population structure in the MSI organoid. G and H, RNA archetypes distribution for MSI and MSS organoids. As expected, drug exposure induces a specific transcriptional phenotype, but the induced instability acts only on the population structure, with minimal influence on the transcriptome. lpWGS, low-pass WGS.