RNA-Seq of Ahr knockout mouse colonic organoids carrying Apc and Kras mutations. Mus musculus

Aryl hydrocarbon receptor (AhR), a ligand-activated basic helix-loop-helix transcription factor that binds structurally diverse ligands and senses cues from environmental toxicants and dietary/microbiota-derived physiologically relevant ligands, is increasingly recognized as a key regulator of intestinal cancer. Our studies found that AhR knockout (KO) promoted the percentage and clonogenic capacity of colonic stem cells carrying ApcS580/+; KrasG12D/+ mutations, and increased cecum and colon tumorigenesis in compound mice carrying those mutations. To systematically investigate how AhR deletion increased the functionality of colonic cancer stem cells, we performed RNAseq from colonic organoids harboring ApcS580/+; KrasG12D/+ mutations with/without AhR in the presence or absence of AhR agonist, TCDD (10 nM) for 1 day. Consistently, we found that AhR KO increased the enrichment of INTESTINAL STEM CELL and SANSOM_APC_TARGETS signature, while AhR activation by TCDD exerted opposite effects. Hence, there findings provide new mechanistic insight into how AhR signaling modulates the functionality of colonic cancer stem cells.