Lineage Plasticity Driven by GATA6 Loss Fuels Colorectal Cancer Metastasis [ATAC-seq_met]

Colorectal cancer (CRC) liver metastases are the leading cause of CRC-related mortality, yet the specific genetic and epigenetic drivers that promote this process remain poorly understood. Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of organoids derived from mouse liver metastases. Integrative RNA-seq and ATAC-seq analyses of these organoids uncovered distinct transcriptomic and chromatin accessibility profiles correlating with metastatic potential. These pro-metastatic epigenetic changes were characterized by reactivation of fetal-like programs and downregulation of LGR5+ intestinal stem cell signatures. Notably, they converged on the silencing of the transcription factor GATA6, which occurs in liver metastases in both mice and humans. Genetic ablation of GATA6 in mouse models significantly enhanced liver metastasis while having minimal impact on primary tumor growth. Mechanistically, the loss of GATA6 induced the pro-metastatic epigenetic state and promoted the generation of LGR5- cancer cells. Together, these findings demonstrate that GATA6 loss drives liver metastatic progression by reprogramming cancer cells into a pro-metastatic epigenetic state through the hijacking of developmental programs.