Rather than epithelial-mesenchymal transition (EMT), epithelial-mesenchymal plasticity (EMP) is now being pushed to the frontline as an in vivo causal factor in malignant tumour progression. Our current understanding of EMP-programs is biased by earlier research focussing on EMT induced by TGFβ1 or a select set of EMT-transcription factors. To improve understanding of EMP in cancer, we developed a novel method to identify in vivo EMP-related genes in an unbiased manner. Using our method, we identified 187 EMP-related genes. We now have access to archived tumour sections and matched scRNA-seq data of paired tumour and healthy tissue of 63 colorectal cancer patients. We will investigate the interaction between the tumour micro-environment and EMP by combining spatial information of highly multiplexed staining, the available scRNA-seq data, predictive modelling, and in vitro validation. A second work package focuses on the role of non-canonical STAT1 signalling in EMP. Target genes of the U-ISGF3 complex, consisting of unphosphorylated STAT1, STAT2, and IRF9 were highly enriched in the EMP-associated genes we identified. Experimental data of EMT-models in human colorectal cancer cell lines strongly supports such a role for U-ISGF3 signalling. We aim to elucidate how U-ISGF3 signalling affects EMP and its functional consequences in colorectal cancer. Lastly, we aim to elucidate the mechanism of action of CDK-8 inhibitors shown to supress both U-ISGF3 target genes and EMP/EMT.