Identification of a clinically relevant signature for early progression in KRAS-driven lung adenocarcinoma

Neidler, S. et al. (2019) Identification of a clinically relevant signature for early progression in KRAS-driven lung adenocarcinoma. Cancers, 11(5), 600. (doi: 10.3390/cancers11050600) (PMID:31032816) (PMCID:PMC6562816)

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Inducible genetically defined mouse models of cancer uniquely facilitate the investigation of early events in cancer progression, however, there are valid concerns about the ability of such models to faithfully recapitulate human disease. We developed an inducible mouse model of progressive lung adenocarcinoma (LuAd) that combines sporadic activation of oncogenic KRasG12D with modest overexpression of c-MYC (KM model). Histological examination revealed a highly reproducible spontaneous transition from low-grade adenocarcinoma to locally invasive adenocarcinoma within 6 weeks of oncogene activation. Laser-capture microdissection coupled with RNA-SEQ (ribonucleic acid sequencing) was employed to determine transcriptional changes associated with tumour progression. Upregulated genes were triaged for relevance to human LuAd using datasets from Oncomine and cBioportal. Selected genes were validated by RNAi screening in human lung cancer cell lines and examined for association with lung cancer patient overall survival using Depletion of progression-associated genes resulted in pronounced viability and/or cell migration defects in human lung cancer cells. Progression-associated genes moreover exhibited strong associations with overall survival, specifically in human lung adenocarcinoma, but not in squamous cell carcinoma. The KM mouse model faithfully recapitulates key molecular events in human adenocarcinoma of the lung and is a useful tool for mechanistic interrogation of KRAS-driven LuAd progression.

Item Type:Articles
Additional Information:Funding for this work was provided by the British Lung Foundation (CSOBLF16-2), Cancer Research UK (C48702/A27603), a Merck, Sharp & Dohme MINT collaborative agreement, European Commission Marie Curie mobility fellowships FP7-CIG-618448 (all to D.J.M.) & H2020-MCSA-705190 (B.K.), & Deutsche Krebshilfe grant 109220 (D.J.M.). T. M. was supported by BLF PhD studentship APHD13-5. Specialist equipment was funded by a generous donation from the M.J.M. Smith Trust (Glasgow). A.H., D.J., W.C. & E.S. and the Beatson Institute screening and sequencing facilities were funded via CRUK core grant A17196.
Glasgow Author(s) Enlighten ID:Monteverde, Tiziana and Gyuraszova, Dr Katarina and Murphy, Professor Daniel and Dick, Dr Craig and Neidler, Ms Sarah and Shanks, Dr Emma and James, Mr Daniel and Clark, Mr William and Hedley, Ms Barbara and Hewit, Dr Kay and Kruspig, Dr Bjorn
Authors: Neidler, S., Kruspig, B., Hewit, K., Monteverde, T., Gyuraszova, K., Braun, A., Clark, W., James, D., Hedley, B., Nieswandt, B., Shanks, E., Dick, C., and Murphy, D. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Cancers
ISSN (Online):2072-6694
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Cancers 11(5):600
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
738121Pre-clinical evaluation of pan-ERBB inhibition to treat KRAS mutant NSCLCDaniel MurphyBritish Lung Foundation (BLF)CSOBLFRG16-2RI CANCER SCIENCES
632881SERPLUC: Suppression of Enzymes Required for Progression of Lung CancerDaniel MurphyEuropean Commission (EC)618448RI CANCER SCIENCES
717931NuSiCCDaniel MurphyEuropean Commission (EC)705190RI CANCER SCIENCES
631971A versatile spatio-temporally inducible genetically engineered mouse model of mesotheliomaDaniel MurphyBritish Lung Foundation (BLF)APHD13-5RI CANCER SCIENCES