Cargando…

Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data

Mice, especially A/J mice, have been widely employed to elucidate the underlying mechanisms of lung tumor formation and progression and to derive human-relevant modes of action. Cigarette smoke (CS) exposure induces tumors in the lungs; but, non-exposed A/J mice will also develop lung tumors spontan...

Descripción completa

Detalles Bibliográficos
Autores principales: Xiang, Yang, Luettich, Karsta, Martin, Florian, Battey, James N. D., Trivedi, Keyur, Neau, Laurent, Wong, Ee Tsin, Guedj, Emmanuel, Dulize, Remi, Peric, Dariusz, Bornand, David, Ouadi, Sonia, Sierro, Nicolas, Büttner, Ansgar, Ivanov, Nikolai V., Vanscheeuwijck, Patrick, Hoeng, Julia, Peitsch, Manuel C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915865/
https://www.ncbi.nlm.nih.gov/pubmed/35295134
http://dx.doi.org/10.3389/ftox.2021.634035
_version_ 1784668150126608384
author Xiang, Yang
Luettich, Karsta
Martin, Florian
Battey, James N. D.
Trivedi, Keyur
Neau, Laurent
Wong, Ee Tsin
Guedj, Emmanuel
Dulize, Remi
Peric, Dariusz
Bornand, David
Ouadi, Sonia
Sierro, Nicolas
Büttner, Ansgar
Ivanov, Nikolai V.
Vanscheeuwijck, Patrick
Hoeng, Julia
Peitsch, Manuel C.
author_facet Xiang, Yang
Luettich, Karsta
Martin, Florian
Battey, James N. D.
Trivedi, Keyur
Neau, Laurent
Wong, Ee Tsin
Guedj, Emmanuel
Dulize, Remi
Peric, Dariusz
Bornand, David
Ouadi, Sonia
Sierro, Nicolas
Büttner, Ansgar
Ivanov, Nikolai V.
Vanscheeuwijck, Patrick
Hoeng, Julia
Peitsch, Manuel C.
author_sort Xiang, Yang
collection PubMed
description Mice, especially A/J mice, have been widely employed to elucidate the underlying mechanisms of lung tumor formation and progression and to derive human-relevant modes of action. Cigarette smoke (CS) exposure induces tumors in the lungs; but, non-exposed A/J mice will also develop lung tumors spontaneously with age, which raises the question of discriminating CS-related lung tumors from spontaneous ones. However, the challenge is that spontaneous tumors are histologically indistinguishable from the tumors occurring in CS-exposed mice. We conducted an 18-month inhalation study in A/J mice to assess the impact of lifetime exposure to Tobacco Heating System (THS) 2.2 aerosol relative to exposure to 3R4F cigarette smoke (CS) on toxicity and carcinogenicity endpoints. To tackle the above challenge, a 13-gene gene signature was developed based on an independent A/J mouse CS exposure study, following by a one-class classifier development based on the current study. Identifying gene signature in one data set and building classifier in another data set addresses the feature/gene selection bias which is a well-known problem in literature. Applied to data from this study, this gene signature classifier distinguished tumors in CS-exposed animals from spontaneous tumors. Lung tumors from THS 2.2 aerosol-exposed mice were significantly different from those of CS-exposed mice but not from spontaneous tumors. The signature was also applied to human lung adenocarcinoma gene expression data (from The Cancer Genome Atlas) and discriminated cancers in never-smokers from those in ever-smokers, suggesting translatability of our signature genes from mice to humans. A possible application of this gene signature is to discriminate lung cancer patients who may benefit from specific treatments (i.e., EGFR tyrosine kinase inhibitors). Mutational spectra from a subset of samples were also utilized for tumor classification, yielding similar results. “Landscaping” the molecular features of A/J mouse lung tumors highlighted, for the first time, a number of events that are also known to play a role in human lung tumorigenesis, such as Lrp1b mutation and Ros1 overexpression. This study shows that omics and computational tools provide useful means of tumor classification where histopathological evaluation alone may be unsatisfactory to distinguish between age- and exposure-related lung tumors.
format Online
Article
Text
id pubmed-8915865
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-89158652022-03-15 Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data Xiang, Yang Luettich, Karsta Martin, Florian Battey, James N. D. Trivedi, Keyur Neau, Laurent Wong, Ee Tsin Guedj, Emmanuel Dulize, Remi Peric, Dariusz Bornand, David Ouadi, Sonia Sierro, Nicolas Büttner, Ansgar Ivanov, Nikolai V. Vanscheeuwijck, Patrick Hoeng, Julia Peitsch, Manuel C. Front Toxicol Toxicology Mice, especially A/J mice, have been widely employed to elucidate the underlying mechanisms of lung tumor formation and progression and to derive human-relevant modes of action. Cigarette smoke (CS) exposure induces tumors in the lungs; but, non-exposed A/J mice will also develop lung tumors spontaneously with age, which raises the question of discriminating CS-related lung tumors from spontaneous ones. However, the challenge is that spontaneous tumors are histologically indistinguishable from the tumors occurring in CS-exposed mice. We conducted an 18-month inhalation study in A/J mice to assess the impact of lifetime exposure to Tobacco Heating System (THS) 2.2 aerosol relative to exposure to 3R4F cigarette smoke (CS) on toxicity and carcinogenicity endpoints. To tackle the above challenge, a 13-gene gene signature was developed based on an independent A/J mouse CS exposure study, following by a one-class classifier development based on the current study. Identifying gene signature in one data set and building classifier in another data set addresses the feature/gene selection bias which is a well-known problem in literature. Applied to data from this study, this gene signature classifier distinguished tumors in CS-exposed animals from spontaneous tumors. Lung tumors from THS 2.2 aerosol-exposed mice were significantly different from those of CS-exposed mice but not from spontaneous tumors. The signature was also applied to human lung adenocarcinoma gene expression data (from The Cancer Genome Atlas) and discriminated cancers in never-smokers from those in ever-smokers, suggesting translatability of our signature genes from mice to humans. A possible application of this gene signature is to discriminate lung cancer patients who may benefit from specific treatments (i.e., EGFR tyrosine kinase inhibitors). Mutational spectra from a subset of samples were also utilized for tumor classification, yielding similar results. “Landscaping” the molecular features of A/J mouse lung tumors highlighted, for the first time, a number of events that are also known to play a role in human lung tumorigenesis, such as Lrp1b mutation and Ros1 overexpression. This study shows that omics and computational tools provide useful means of tumor classification where histopathological evaluation alone may be unsatisfactory to distinguish between age- and exposure-related lung tumors. Frontiers Media S.A. 2021-03-16 /pmc/articles/PMC8915865/ /pubmed/35295134 http://dx.doi.org/10.3389/ftox.2021.634035 Text en Copyright © 2021 Xiang, Luettich, Martin, Battey, Trivedi, Neau, Wong, Guedj, Dulize, Peric, Bornand, Ouadi, Sierro, Büttner, Ivanov, Vanscheeuwijck, Hoeng and Peitsch. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Toxicology
Xiang, Yang
Luettich, Karsta
Martin, Florian
Battey, James N. D.
Trivedi, Keyur
Neau, Laurent
Wong, Ee Tsin
Guedj, Emmanuel
Dulize, Remi
Peric, Dariusz
Bornand, David
Ouadi, Sonia
Sierro, Nicolas
Büttner, Ansgar
Ivanov, Nikolai V.
Vanscheeuwijck, Patrick
Hoeng, Julia
Peitsch, Manuel C.
Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data
title Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data
title_full Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data
title_fullStr Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data
title_full_unstemmed Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data
title_short Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data
title_sort discriminating spontaneous from cigarette smoke and ths 2.2 aerosol exposure-related proliferative lung lesions in a/j mice by using gene expression and mutation spectrum data
topic Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915865/
https://www.ncbi.nlm.nih.gov/pubmed/35295134
http://dx.doi.org/10.3389/ftox.2021.634035
work_keys_str_mv AT xiangyang discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT luettichkarsta discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT martinflorian discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT batteyjamesnd discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT trivedikeyur discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT neaulaurent discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT wongeetsin discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT guedjemmanuel discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT dulizeremi discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT pericdariusz discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT bornanddavid discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT ouadisonia discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT sierronicolas discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT buttneransgar discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT ivanovnikolaiv discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT vanscheeuwijckpatrick discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT hoengjulia discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata
AT peitschmanuelc discriminatingspontaneousfromcigarettesmokeandths22aerosolexposurerelatedproliferativelunglesionsinajmicebyusinggeneexpressionandmutationspectrumdata