title: Characterization of a genetic mouse model of lung cancer: a promise to identify Non-Small Cell Lung Cancer therapeutic targets and biomarkers.
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.
authors: Federica
authors: F
authors: Riccardo
authors: Maddalena
authors: M
authors: Arigoni
authors: Genny
authors: G
authors: Buson
authors: Elisa
authors: E
authors: Zago
authors: Manuela
authors: M
authors: Iezzi
authors: Dario
authors: D
authors: Longo
authors: Matteo
authors: M
authors: Carrara
authors: Alessandra
authors: A
authors: Fiore
authors: Simona
authors: S
authors: Nuzzo
authors: Silvio
authors: S
authors: Bicciato
authors: Patrizia
authors: P
authors: Nanni
authors: Lorena
authors: L
authors: Landuzzi
authors: Federica
authors: F
authors: Cavallo
authors: Raffaele
authors: R
authors: Calogero
authors: Elena
authors: E
authors: Quaglino
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D016158:Genes, p53; D011905:Genes, ras; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D053495:Osteopontin / Q000235:genetics; D011379:Prognosis; D059467:Transcriptome; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; C506895:SPP1 protein, human; D053495:Osteopontin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor