Fig. 6
AhR displays a pro-tumorigenic activity in luminal bladder cancer (BCa). a Cancer effect size for AHR mutations in BCa. Mutations were clustered into two groups based on cancer effect sizes (low or high). Mutations with determined functional impact were computationally added for reference. b Heatmap showing relationships among tumour molecular classes, AHR/ARNT gene expression, AHR/ARNT genetic alterations and AhR regulon activity. c Association between AHR/ARNT genetic alterations (mutations and amplifications) and AhR activity in BCa. AhR activity was calculated using gene set variation analysis (GSVA) based on AhR regulon in BCa tumours (‘Methods’). P values were from Kruskal’s test across groups and Dunn’s test with FDR adjustment for pairwise comparisons. d Distribution of AHR/ARNT genetic alterations (mutations and amplifications) in BCa tumours. Tumour molecular classes are based on a recently published consensus classification of BCa [44], where luminal papillary, luminal unstable and luminal non-specified tumours were grouped as ‘luminal’ (n = 202) and others as ‘non-luminal’ (n = 204) (‘Methods’). P value: Fisher’s exact test. e Correlation between AHR and ARNT dependency among BCa cell lines was evaluated (Pearson’s correlation, R = 0.78, P = 9 × 10− 7). Cell viability dependency scores to AHR and ARNT knockout (using CRISPR-cas9) in BCa cell lines were available from the DepMap data repository (20Q2 version, n = 28) [49]. AHR/ARNT genetic alterations and subtypes were colour-coded and symbol-coded, respectively. f Response to AhR inhibition in BCa-derived cell lines (n = 10). CH-223191 is an AhR-specific inhibitor. All cells were treated for 72 h with either DMSO or following inhibitor concentration: 1.25, 2.5, 5, 10, 20 μM. Cell viability is measured by CellTiter-Glo assay and is shown as normalised between inhibitor treatment and DMSO control. KMBC2 and UMUC7 cells, both classified as luminal type, harbour the AHR Q383H mutation (in pink) and an AHR amplification (in orange), respectively; Other luminal cells included UMUC14, RT112 and RT4, and the remaining cells were classified as non-luminal group (‘Methods’)