1. Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis
- Author
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Madeleine Dorsch, Martin Schuler, Clotilde Thumser-Henner, Frank Breitenbücher, Sophie Kalmbach, Alexander Schramm, Jan Forster, Christiane A. Opitz, Ahmed Sadik, Saurabh Asthana, Trever G. Bivona, Ross A. Okimoto, Silke Nothdurft, Barbara M. Grüner, Daniela Beisser, Michael Hölzel, and Charlotte Esser
- Subjects
0301 basic medicine ,Cancer Research ,Oncology and Carcinogenesis ,Medizin ,Matrix metalloproteinase ,lcsh:RC254-282 ,Article ,Metastasis ,Small hairpin RNA ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Cancer models ,Lung cancer ,Molecular Biology ,Transcription factor ,Lung ,Cancer ,Gene knockdown ,biology ,business.industry ,Prevention ,Lung Cancer ,respiratory system ,medicine.disease ,Aryl hydrocarbon receptor ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Biochemistry and Cell Biology ,business ,Non-small-cell lung cancer ,Biologie - Abstract
Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial–mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.
- Published
- 2020