PT Unknown AU Nothdurft, S TI Identification and characterization of aryl hydrocarbon receptor (AHR) as a suppressor of non-small-cell lung cancer metastasis PD 08 PY 2020 DI 10.17185/duepublico/71562 LA en AB Lung cancer is the leading cause of cancer-related deaths worldwide. Lung cancer mortality is mainly caused from metastatic progression. The majority of patients presents with metastatic disease at primary diagnosis. In addition, a substantial fraction of patients comes down with metastatic relapse despite potentially curative treatment of localized disease. Lung cancers are histologically classified as small cell (SCLC) and non-small-cell lung cancers (NSCLC). Adenocarcinomas and squamous cell carcinomas are the largest subgroups of NSCLC. Current strategies to reduce the risk of metastatic relapse in early stage NSCLC rely on adjuvant cisplatin-based chemotherapy and radiation though having only modest activity. There are no therapeutic or preventive approaches specifically tailored to modulation of metastasis. This is in part due to still limited understanding of the metastatic process itself and the lack of defined molecular targets for anti-metastatic interventions. Against this background, we used an in vivo shRNA screening platform in an orthotopic mouse model of lung cancer to identify candidate metastasis-modulators. Among these, aryl hydrocarbon receptor (AHR), a ligand-regulated transcription factor and sensor of xenobiotics, was prioritized and subjected to functional and mechanistic validation in this thesis. In the NCI-H1975 lung adenocarcinoma model, shRNA-mediated suppression of AHR expression increased metastatic potential in vitro and promoted metastases formation in an orthotopic lung cancer model in vivo. Importantly, low intratumoral AHR expression correlated with inferior survival and decreased time to progression in patients with locally or locally advanced lung cancer. Analysis of constitutive and AHR-ligand activated RNA expression profiles revealed a negative correlation of AHR expression and EMT signatures including several genes encoding matrix-metalloproteases. Activation of AHR by its ligand omeprazole induced expression of ASNS and ATF4, both encoding gene products that are involved in the cellular stress response. Interestingly, ASNS induction was ATF4-dependent and attenuated in AHR-deficient NCI-H1975 exhibiting increased metastatic potential. Moreover, AHR knockdown conferred increased resistance to glutamine-depleted growth conditions. These findings identify AHR and AHR-regulated pathways as promising targets for rational anti-metastatic interventions in NSCLC. ER