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

Sarah Neidler; Björn Kruspig; Kay Hewit; Tiziana Monteverde; Katarina Gyuraszova; Attila Braun; William Clark; Daniel James; Ann Hedley; Bernhard Nieswandt; Emma Shanks; Craig Dick; Daniel J. Murphy

doi:10.20944/preprints201903.0286.v1

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preprints.org > biology and life sciences > biochemistry and molecular biology > doi: 10.20944/preprints201903.0286.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 28 March 2019 / Approved: 30 March 2019 / Online: 30 March 2019 (06:41:07 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

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 KRas^G12D with modest overexpression of c-MYC (KM model). Histological examination revealed a highly reproducible transition from adenoma to locally invasive adenocarcinoma within 6 weeks of oncogene activation. Laser-capture microdissection coupled with RNA-SEQ 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 lung cancer and is a useful tool for mechanistic interrogation of LuAd progression.

Keywords

lung adenocarcinoma; KRAS; MYC; ERBB; mouse models of cancer; RNA-SEQ

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Comments (2)

Comment 1

Received: 30 March 2019
Commenter:

Daniel Murphy

The commenter has declared there is no conflict of interests.

Comment: Apologies to anyone who has already viewed the manuscript, as key labels are missing from Figures 2C and S1A. I will upload corrected figures shortly.

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Response 1 to Comment 1

Received: 28 April 2019
Commenter:

Daniel Murphy

The commenter has declared there is no conflict of interests.

Comment: The aforementioned issues with the figures have now been resolved

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