Inhibition of a corrupted embryonic developmental regulator reverses colon cancer to a normal-like state [TAF10_bulk_ATAC]

This raises questions about the existence and possible identification of a molecular switch that governs such reversion. We analyzed single-cell transcriptomes from patient-derived paired colon organoids, integrating copy number alterations to delineate a transition state between normal and malignant cells.

Regulatory network analysis of this state identified TAF10 as a reversion switch whose knockdown drives colorectal cancer cells toward a normal-like state, without effecting normal cell growth. Logical network modeling predicted that TAF10 knockdown suppresses oncogenic WNT, mTOR, and MAPK signaling, while activating enterocyte differentiation. Consistent with these predictions, organoid and in vivo assays demonstrated reduced malignancy and increased differentiation.