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

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.