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NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity

Abstract

The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear. We show here that the lung lineage transcription factor NKX2-1 suppresses ERK activity. In human tissue samples and cell lines, xenografts, and genetic mouse models, NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits tumor growth and metastasis. We show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo and that DUSP6 expression is sufficient to inhibit RAS-driven LUAD. Our results indicate that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.

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Fig. 1: NKX2-1 transcriptionally induces DUSP6.
Fig. 2: NKX2-1 inhibits cell proliferation, migration and invasion, and tumor growth, dissemination, and ERK activity.
Fig. 3: NKX2-1 requires DUSP6 to slow cell proliferation and migration.
Fig. 4: NKX2-1 controls tumor progression through DUSP6.

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Acknowledgements

Thanks to Dr. Stephen Keyse for the gift of the DUSP6 promoter constructs and Dr. Doug Mackay for H2B-mCherry-N2. Thanks to Keith Carney for the development of software for automated cell migration tracking. Flow cytometry was supported by the University of Utah Flow Cytometry Facility and funding from 5P30CA042014-24 and 1S10RR026802-01. Thanks to the University of Utah Cell Imaging Core and the Huntsman Cancer Institute Preclinical Research Resource. M.C.M was supported by K01CA168850, R21CA215891, an American Lung Association Research Grant, American Cancer Society RSG CSM130435, and V Scholar Award. E.L.S. was supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a V Scholar Award, and R01CA212415 and R01CA240317.

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ELS and MCM conceptualized the study. KI, SCS, RGZ, RZ, ELS, and MCM carried out the investigation and extraction of the results. SCS, ELS, and MCM designed the methods and carried out formal analysis and interpretation of the results. MCM managed data curation, project administration, acquisition of study funding, and writing the original manuscript draft. All co-authors were involved in review and editing of the manuscript.

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Correspondence to Michelle C. Mendoza.

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Ingram, K., Samson, S.C., Zewdu, R. et al. NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity. Oncogene 41, 293–300 (2022). https://doi.org/10.1038/s41388-021-02076-x

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