Bulk RNA-seq and scRNA-seq of transgenic mouse bladder organoids

Bladder cancer is a common cancer with limited progress in treatment of patients with advanced stages of the disease. Identification of genetic contributors underlying the disease may provide therapeutic approaches. We discovered a novel recurrent in-frame deletion of exons 8 and 9 in the Aryl Hydrocarbon Receptor (AHR) gene with a high prevalence in urinary tract cancer samples. AhR is a ligand-activated transcription factor best known for its cellular response to toxic aromatic hydrocarbons. We examined the consequences of different AHR alterations by stable overexpressing the human mutated AHR sequences in mouse bladder organoids. We show that the AHR alterations activate the canonical AhR pathway and AhR signaling and thereby modulate transcription expression. In particular, the identified hotspot point mutant (AHR Q383H) leads to more sensitized ligand-dependent activation while the detected deletion (AHR ?e8-9) leads to ligand-independent constitutive activation of the AhR pathway thereby promoting bladder cells to adopt a transformed undifferentiated proliferative phenotype. Our results indicate that AHR is a key proto-oncogene and cancer driver in urinary tract cancers and emphasize the potential of the AhR pathway a target for therapeutic interventions.