J. Zaugg, formerly EMBL, now Basel University, and R. Jackstadt propose that complex transcriptional, epigenetic, and microbial changes are interconnected and foster enhanced phenotypic plasticity of metastatic and therapy resistant CRC.They aim to dissect underlying mechanisms that interconnect the microbiome and its metabolome with cell state dynamics and cellular plasticity to define actionable targets. To study longitudinal changes, they will utilise a novel CRISPR-Cas9 somatic genome editing mouse model from the Jackstadt group. Multi-omics analysis on single cell level (epigenome and transcriptome) combined with temporal and functional analysis of the microbiome along the progression of CRC will shed light on the role of the microbiome.Zaugg’s expertise in computational modelling of gene regulatory networks and cellular plasticity will be essential and critical for defining temporal plasticity shaped by the microbiota composition. Together with R. Jackstadt, she will model and functionally validate the impact of the microbiome on the cell state continuum in CRC progression and treatment resistance.