Cargando…
Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma
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 ade...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562816/ https://www.ncbi.nlm.nih.gov/pubmed/31032816 http://dx.doi.org/10.3390/cancers11050600 |
_version_ | 1783426409848373248 |
---|---|
author | Neidler, Sarah Kruspig, Björn Hewit, Kay Monteverde, Tiziana Gyuraszova, Katarina Braun, Attila Clark, William James, Daniel Hedley, Ann Nieswandt, Bernhard Shanks, Emma Dick, Craig Murphy, Daniel J. |
author_facet | Neidler, Sarah Kruspig, Björn Hewit, Kay Monteverde, Tiziana Gyuraszova, Katarina Braun, Attila Clark, William James, Daniel Hedley, Ann Nieswandt, Bernhard Shanks, Emma Dick, Craig Murphy, Daniel J. |
author_sort | Neidler, Sarah |
collection | PubMed |
description | 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 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. |
format | Online Article Text |
id | pubmed-6562816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-65628162019-06-17 Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma Neidler, Sarah Kruspig, Björn Hewit, Kay Monteverde, Tiziana Gyuraszova, Katarina Braun, Attila Clark, William James, Daniel Hedley, Ann Nieswandt, Bernhard Shanks, Emma Dick, Craig Murphy, Daniel J. Cancers (Basel) Article 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 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. MDPI 2019-04-29 /pmc/articles/PMC6562816/ /pubmed/31032816 http://dx.doi.org/10.3390/cancers11050600 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Neidler, Sarah Kruspig, Björn Hewit, Kay Monteverde, Tiziana Gyuraszova, Katarina Braun, Attila Clark, William James, Daniel Hedley, Ann Nieswandt, Bernhard Shanks, Emma Dick, Craig Murphy, Daniel J. Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma |
title | Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma |
title_full | Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma |
title_fullStr | Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma |
title_full_unstemmed | Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma |
title_short | Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma |
title_sort | identification of a clinically relevant signature for early progression in kras-driven lung adenocarcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562816/ https://www.ncbi.nlm.nih.gov/pubmed/31032816 http://dx.doi.org/10.3390/cancers11050600 |
work_keys_str_mv | AT neidlersarah identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT kruspigbjorn identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT hewitkay identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT monteverdetiziana identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT gyuraszovakatarina identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT braunattila identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT clarkwilliam identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT jamesdaniel identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT hedleyann identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT nieswandtbernhard identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT shanksemma identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT dickcraig identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma AT murphydanielj identificationofaclinicallyrelevantsignatureforearlyprogressioninkrasdrivenlungadenocarcinoma |