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Published on: March 7, 2019
Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis
Silke Nothdurft1, Clotilde Thumser-Henner1, Frank Breitenbücher1
1Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
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.
Insights
The aryl hydrocarbon receptor (AHR) suppresses lung cancer metastasis. Lower AHR levels correlate with poorer patient outcomes, suggesting AHR pathways as novel anti-metastasis targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Lung cancer mortality is primarily driven by metastasis.
- Current treatments for early-stage non-small cell lung cancer (NSCLC) have limited efficacy against metastatic relapse.
- Novel therapeutic strategies are needed to combat lung cancer metastasis.
Purpose of the Study:
- To identify novel regulators of lung cancer metastasis.
- To investigate the role of the aryl hydrocarbon receptor (AHR) in lung cancer progression.
Main Methods:
- Functional screening using a barcoded shRNA library.
- Orthotopic lung cancer model for in vivo metastasis assessment.
- In vitro assays for cell invasiveness and epithelial-mesenchymal transition (EMT).
Main Results:
- Aryl hydrocarbon receptor (AHR) was identified as a suppressor of lung cancer metastasis.
- AHR knockdown promoted EMT, increased invasiveness, and enhanced metastasis formation.
- Low intratumoral AHR expression in patients correlated with worse outcomes in resected lung adenocarcinomas.
- AHR activation of ATF4 signaling and repression of matrix metalloproteinase activity were identified as key mechanisms.
Conclusions:
- The xenobiotic sensor Aryl hydrocarbon receptor (AHR) plays a critical role in suppressing lung cancer metastasis.
- AHR-mediated regulation of ATF4 signaling and matrix metalloproteinase activity counteracts metastatic processes.
- AHR-regulated pathways represent promising therapeutic targets for innovative anti-metastatic strategies in lung cancer.
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