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.
Highlights
Lung cancer is the leading cancer fatality at a global level
An unbiased shRNA screen in an orthotopic mouse model of lung cancer reveals metastasis genes To identify metastasis-modulating genes, we performed an unbiased shRNA screen in a model based on EGFRdriven H1975 human lung adenocarcinoma cells, which have low endogenous metastatic potential[11]
While several candidates were identified with varying barcode representation levels, aryl hydrocarbon receptor (AHR) was selected for validation (Fig. 1c) due to its comparable representation pattern in both metastatic tumors that were analyzed
Summary
Despite major improvements in the treatment of patients with advanced lung cancers, the highest impact on reduction of mortality can be expected from prevention and early detection programs. With the imminent implementation of national screening programs an increase in lung cancers detected at early stages that are amenable to curative surgery is expected. While this will significantly contribute to reduction of lung cancer mortality, metastatic relapse will still occur in many of these patients. Current strategies for risk reduction of systemic relapse following lung cancer surgery have evolved by translating platinum-based chemotherapy from the metastatic setting to earlier disease stages[3,4,5]. Its role in resected lung cancer currently is unknown
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