Characterization of a genetic mouse model of lung cancer: a promise to identify Non-Small Cell Lung Cancer therapeutic targets and biomarkers

Federica Riccardo, Maddalena Arigoni, Genny Buson, Elisa Zago, Manuela Iezzi, Dario Longo, Matteo Carrara, Alessandra Fiore, Simona Nuzzo, Silvio Bicciato, Patrizia Nanni, Lorena Landuzzi, Federica Cavallo, Raffaele Calogero, Elena Quaglino

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 81% of all cases of lung cancer and they are often fatal because 60% of the patients are diagnosed at an advanced stage. Besides the need for earlier diagnosis, there is a high need for additional effective therapies. In this work, we investigated the feasibility of a lung cancer progression mouse model, mimicking features of human aggressive NSCLC, as biological reservoir for potential therapeutic targets and biomarkers.

RESULTS: We performed RNA-seq profiling on total RNA extracted from lungs of a 30 week-old K-ras(LA1)/p53(R172HΔg) and wild type (WT) mice to detect fusion genes and gene/exon-level differential expression associated to the increase of tumor mass. Fusion events were not detected in K-ras(LA1)/p53(R172HΔg) tumors. Differential expression at exon-level detected 33 genes with differential exon usage. Among them nine, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of more than 500 NSCLC RNA-seq transcriptomes. None of the genes showed a significant correlation between exon-level expression and disease prognosis. Differential expression at gene-level allowed the identification of 1513 genes with a significant increase in expression associated to tumor mass increase. 74 genes, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of two transcriptomics datasets of human NSCLC samples, encompassing more than 900 samples. SPP1 was the only molecule whose over-expression resulted statistically related to poor outcome regarding both survival and metastasis formation. Two other molecules showed over-expression associated to poor outcome due to metastasis formation: GM-CSF and ADORA3. GM-CSF is a secreted protein, and we confirmed its expression in the supernatant of a cell line derived by a K-ras(LA1)/p53(R172HΔg) mouse tumor. ADORA3 is instead involved in the induction of p53-mediated apoptosis in lung cancer cell lines. Since in our model p53 is inactivated, ADORA3 does not negatively affect tumor growth but remains expressed on tumor cells. Thus, it could represent an interesting target for the development of antibody-targeted therapy on a subset of NSCLC, which are p53 null and ADORA3 positive.

CONCLUSIONS: Our study provided a complete transcription overview of the K-ras(LA1)/p53(R172HΔg) mouse NSCLC model. This approach allowed the detection of ADORA3 as a potential target for antibody-based therapy in p53 mutated tumors.

Original languageEnglish
Pages (from-to)S1
JournalBMC Genomics
Volume15
DOIs
Publication statusPublished - 2014

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Genetic Models
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Biomarkers
Exons
Neoplasms
Genes
RNA
Granulocyte-Macrophage Colony-Stimulating Factor
Therapeutics
Meta-Analysis
Cell Membrane
Neoplasm Metastasis
Cell Line
Antibodies
Gene Fusion
Transcriptome
Early Diagnosis
Apoptosis
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

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Characterization of a genetic mouse model of lung cancer : a promise to identify Non-Small Cell Lung Cancer therapeutic targets and biomarkers. / Riccardo, Federica; Arigoni, Maddalena; Buson, Genny; Zago, Elisa; Iezzi, Manuela; Longo, Dario; Carrara, Matteo; Fiore, Alessandra; Nuzzo, Simona; Bicciato, Silvio; Nanni, Patrizia; Landuzzi, Lorena; Cavallo, Federica; Calogero, Raffaele; Quaglino, Elena.

In: BMC Genomics, Vol. 15, 2014, p. S1.

Research output: Contribution to journalArticle

Riccardo, F, Arigoni, M, Buson, G, Zago, E, Iezzi, M, Longo, D, Carrara, M, Fiore, A, Nuzzo, S, Bicciato, S, Nanni, P, Landuzzi, L, Cavallo, F, Calogero, R & Quaglino, E 2014, 'Characterization of a genetic mouse model of lung cancer: a promise to identify Non-Small Cell Lung Cancer therapeutic targets and biomarkers', BMC Genomics, vol. 15, pp. S1. https://doi.org/10.1186/1471-2164-15-S3-S1
Riccardo, Federica ; Arigoni, Maddalena ; Buson, Genny ; Zago, Elisa ; Iezzi, Manuela ; Longo, Dario ; Carrara, Matteo ; Fiore, Alessandra ; Nuzzo, Simona ; Bicciato, Silvio ; Nanni, Patrizia ; Landuzzi, Lorena ; Cavallo, Federica ; Calogero, Raffaele ; Quaglino, Elena. / Characterization of a genetic mouse model of lung cancer : a promise to identify Non-Small Cell Lung Cancer therapeutic targets and biomarkers. In: BMC Genomics. 2014 ; Vol. 15. pp. S1.
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T2 - a promise to identify Non-Small Cell Lung Cancer therapeutic targets and biomarkers

AU - Riccardo, Federica

AU - Arigoni, Maddalena

AU - Buson, Genny

AU - Zago, Elisa

AU - Iezzi, Manuela

AU - Longo, Dario

AU - Carrara, Matteo

AU - Fiore, Alessandra

AU - Nuzzo, Simona

AU - Bicciato, Silvio

AU - Nanni, Patrizia

AU - Landuzzi, Lorena

AU - Cavallo, Federica

AU - Calogero, Raffaele

AU - Quaglino, Elena

PY - 2014

Y1 - 2014

N2 - BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 81% of all cases of lung cancer and they are often fatal because 60% of the patients are diagnosed at an advanced stage. Besides the need for earlier diagnosis, there is a high need for additional effective therapies. In this work, we investigated the feasibility of a lung cancer progression mouse model, mimicking features of human aggressive NSCLC, as biological reservoir for potential therapeutic targets and biomarkers.RESULTS: We performed RNA-seq profiling on total RNA extracted from lungs of a 30 week-old K-ras(LA1)/p53(R172HΔg) and wild type (WT) mice to detect fusion genes and gene/exon-level differential expression associated to the increase of tumor mass. Fusion events were not detected in K-ras(LA1)/p53(R172HΔg) tumors. Differential expression at exon-level detected 33 genes with differential exon usage. Among them nine, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of more than 500 NSCLC RNA-seq transcriptomes. None of the genes showed a significant correlation between exon-level expression and disease prognosis. Differential expression at gene-level allowed the identification of 1513 genes with a significant increase in expression associated to tumor mass increase. 74 genes, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of two transcriptomics datasets of human NSCLC samples, encompassing more than 900 samples. SPP1 was the only molecule whose over-expression resulted statistically related to poor outcome regarding both survival and metastasis formation. Two other molecules showed over-expression associated to poor outcome due to metastasis formation: GM-CSF and ADORA3. GM-CSF is a secreted protein, and we confirmed its expression in the supernatant of a cell line derived by a K-ras(LA1)/p53(R172HΔg) mouse tumor. ADORA3 is instead involved in the induction of p53-mediated apoptosis in lung cancer cell lines. Since in our model p53 is inactivated, ADORA3 does not negatively affect tumor growth but remains expressed on tumor cells. Thus, it could represent an interesting target for the development of antibody-targeted therapy on a subset of NSCLC, which are p53 null and ADORA3 positive.CONCLUSIONS: Our study provided a complete transcription overview of the K-ras(LA1)/p53(R172HΔg) mouse NSCLC model. This approach allowed the detection of ADORA3 as a potential target for antibody-based therapy in p53 mutated tumors.

AB - BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 81% of all cases of lung cancer and they are often fatal because 60% of the patients are diagnosed at an advanced stage. Besides the need for earlier diagnosis, there is a high need for additional effective therapies. In this work, we investigated the feasibility of a lung cancer progression mouse model, mimicking features of human aggressive NSCLC, as biological reservoir for potential therapeutic targets and biomarkers.RESULTS: We performed RNA-seq profiling on total RNA extracted from lungs of a 30 week-old K-ras(LA1)/p53(R172HΔg) and wild type (WT) mice to detect fusion genes and gene/exon-level differential expression associated to the increase of tumor mass. Fusion events were not detected in K-ras(LA1)/p53(R172HΔg) tumors. Differential expression at exon-level detected 33 genes with differential exon usage. Among them nine, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of more than 500 NSCLC RNA-seq transcriptomes. None of the genes showed a significant correlation between exon-level expression and disease prognosis. Differential expression at gene-level allowed the identification of 1513 genes with a significant increase in expression associated to tumor mass increase. 74 genes, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of two transcriptomics datasets of human NSCLC samples, encompassing more than 900 samples. SPP1 was the only molecule whose over-expression resulted statistically related to poor outcome regarding both survival and metastasis formation. Two other molecules showed over-expression associated to poor outcome due to metastasis formation: GM-CSF and ADORA3. GM-CSF is a secreted protein, and we confirmed its expression in the supernatant of a cell line derived by a K-ras(LA1)/p53(R172HΔg) mouse tumor. ADORA3 is instead involved in the induction of p53-mediated apoptosis in lung cancer cell lines. Since in our model p53 is inactivated, ADORA3 does not negatively affect tumor growth but remains expressed on tumor cells. Thus, it could represent an interesting target for the development of antibody-targeted therapy on a subset of NSCLC, which are p53 null and ADORA3 positive.CONCLUSIONS: Our study provided a complete transcription overview of the K-ras(LA1)/p53(R172HΔg) mouse NSCLC model. This approach allowed the detection of ADORA3 as a potential target for antibody-based therapy in p53 mutated tumors.

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