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Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis
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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677369/ https://www.ncbi.nlm.nih.gov/pubmed/33214553 http://dx.doi.org/10.1038/s41389-020-00286-8 |
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author | Nothdurft, Silke Thumser-Henner, Clotilde Breitenbücher, Frank Okimoto, Ross A. Dorsch, Madeleine Opitz, Christiane A. Sadik, Ahmed Esser, Charlotte Hölzel, Michael Asthana, Saurabh Forster, Jan Beisser, Daniela Kalmbach, Sophie Grüner, Barbara M. Bivona, Trever G. Schramm, Alexander Schuler, Martin |
author_facet | Nothdurft, Silke Thumser-Henner, Clotilde Breitenbücher, Frank Okimoto, Ross A. Dorsch, Madeleine Opitz, Christiane A. Sadik, Ahmed Esser, Charlotte Hölzel, Michael Asthana, Saurabh Forster, Jan Beisser, Daniela Kalmbach, Sophie Grüner, Barbara M. Bivona, Trever G. Schramm, Alexander Schuler, Martin |
author_sort | Nothdurft, Silke |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7677369 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76773692020-11-20 Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis Nothdurft, Silke Thumser-Henner, Clotilde Breitenbücher, Frank Okimoto, Ross A. Dorsch, Madeleine Opitz, Christiane A. Sadik, Ahmed Esser, Charlotte Hölzel, Michael Asthana, Saurabh Forster, Jan Beisser, Daniela Kalmbach, Sophie Grüner, Barbara M. Bivona, Trever G. Schramm, Alexander Schuler, Martin Oncogenesis Article 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. Nature Publishing Group UK 2020-11-19 /pmc/articles/PMC7677369/ /pubmed/33214553 http://dx.doi.org/10.1038/s41389-020-00286-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Nothdurft, Silke Thumser-Henner, Clotilde Breitenbücher, Frank Okimoto, Ross A. Dorsch, Madeleine Opitz, Christiane A. Sadik, Ahmed Esser, Charlotte Hölzel, Michael Asthana, Saurabh Forster, Jan Beisser, Daniela Kalmbach, Sophie Grüner, Barbara M. Bivona, Trever G. Schramm, Alexander Schuler, Martin Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis |
title | Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis |
title_full | Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis |
title_fullStr | Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis |
title_full_unstemmed | Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis |
title_short | Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis |
title_sort | functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677369/ https://www.ncbi.nlm.nih.gov/pubmed/33214553 http://dx.doi.org/10.1038/s41389-020-00286-8 |
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