Phenotypic plasticity mediates colorectal cancer metastasis

A major challenge for inhibiting metastasis is the ability of cancer cells to reversibly switch states in response to microenvironmental cues along the metastatic cascade. The regulatory factors and signals from the microenvironment enabling colorectal cancer (CRC) cells to transition into an invasive state and to establish metastasis in the liver remain unknown. Using a combination of single-cell multiomics and spatial transcriptomics data from primary and metastatic CRC patients, we reveal putative metastasis-initiating cancer states with regenerative and inflammatory signatures, driven by transcription factors AP-1, NF-κB and YAP. We demonstrate the existence of an intermediate population with a hybrid regenerative and stem phenotype, indicating phenotypic transitions between stem and pro-metastatic cells. Our spatial analyses show localisation of the regenerative states at the invasive edge in primary CRC and in an immunosuppressive niche in liver metastasis, surrounded by immune and stromal cells that sustain these cells. We uncover putative ligand-receptor interactions driven by cancer-associated fibroblasts (CAFs), macrophages and CD8 T cells that activate the regenerative and inflammatory invasive phenotype in cancer cells. Together, our findings reveal regulatory and signalling factors that can be targeted to restrict transition into invasive states to impair metastasis.