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Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma

1
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
2
CRUK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK
3
Institute of Experimental Biomedicine, University Hospital Wuerzburg, DE 97080 Wuerzburg, Germany
4
Rudolf Virchow Center, Julius Maxmilians University of Wuerzburg, DE 97080 Wuerzburg, Germany
5
Queen Elizabeth University Hospital, Glasgow G51 4TF, UK
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 600; https://doi.org/10.3390/cancers11050600
Received: 24 March 2019 / Revised: 16 April 2019 / Accepted: 28 April 2019 / Published: 29 April 2019
(This article belongs to the Special Issue Molecular Profiling of Lung Cancer)
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Abstract

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 KMplot.com. 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. View Full-Text
Keywords: lung adenocarcinoma; KRAS; MYC; ERBB; Mouse models of cancer; RNA-SEQ lung adenocarcinoma; KRAS; MYC; ERBB; Mouse models of cancer; RNA-SEQ
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Neidler, S.; Kruspig, B.; Hewit, K.; Monteverde, T.; Gyuraszova, K.; Braun, A.; Clark, W.; James, D.; Hedley, A.; Nieswandt, B.; Shanks, E.; Dick, C.; Murphy, D.J. Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma. Cancers 2019, 11, 600.

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