Lineage Plasticity Driven by GATA6 Loss Fuels Colorectal Cancer Metastasis [GATA6_CUT&RUN]

Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of liver metastasis–derived organoids. Integrative RNA-seq and ATAC-seq analyses identified a pro-metastatic signature characterized by multilineage plasticity, including fetal-like and basal-like/squamous transcriptional programs.

Motif and transcription factor activity analyses identified GATA6 as a key regulator of these epigenetic alterations. GATA6 expression is downregulated in liver metastases, and its genetic ablation enhances liver metastasis with minimal effects on primary tumor growth. Mechanistically, GATA6 loss triggers pro-metastatic transcriptional programs, including fetal-like and basal-like/squamous states, accompanied by LGR5⁻ cell generation.