Understanding the complex biology of AHR activation in cancer

ongoing

The aryl hydrocarbon receptor (AHR) is a critical regulator of tumor progression by modulating both tumor cell intrinsic malignant properties as well as anti-tumor immunity. However, depending on the context, the AHR can exert either tumor-promoting or tumor-suppressive effects, thus limiting its potential as a drug target. To exploit the AHR for cancer therapy a comprehensive understanding of its activation and biological outcomes is necessary. The opposing effects of the AHR in cancer likely stem from the complexity of its activation and biological functions, which are cell type-, ligand-, and context-specific. Moreover, recent results from our laboratory suggest that nutritional stress conditions also affect AHR activity. The detection of AHR activation in tissues mainly relies on the quantitation of AHR target gene expression. However, until recently, the context specificity of AHR target gene expression had impeded systematic investigation of AHR activity across human cancers. Our team has developed a pan-tissue AHR signature that detects AHR activity irrespective of cell type or ligand, and enables the analysis of the biological functions mediated through AHR activation. The combination of the AHR signature with iterative cycles of computational biology analyses and laboratory experimentation puts us in a unique position to investigate AHR activation and its downstream effects. CancAHR will hence systematically delineate how the AHR is activated in cancer, why AHR activation is cell type-specific, and which AHR downstream mediators drive clinical outcomes. The identification of the molecular mechanisms underlying the diverse outcomes of AHR activation in cancer will enable (i) the identification of patients, in which AHR activation contributes to clinical outcome; (ii) the development of clinical interventions tailored to the specific mechanisms of AHR activation; and (iii) stratification of patients to precision therapies modulating AHR activity.