Abstract 3166: Lung cancer bio-signatures in plasma based on the analysis of mouse models

Abstract

Abstract Genetically engineered mouse models of cancer have been shown to recapitulate many of the molecular and biological features of human cancer. To identify plasma proteins that show altered abundance during lung cancer development, we applied in-depth quantitative proteomic analysis to plasma from three mouse models of lung adenocarcinoma driven by mutant EGFR, Kras or induced by urethane exposure; a mouse model of small cell lung cancer (SCLC); models of pancreatic, ovarian, colon, prostate and breast cancer; and two mouse models of inflammatory disease as confounders. Plasma proteins from mice with disease and age-matched littermate controls were analyzed by mass spectrometry (MS). Whole cell lysates and conditioned media from 12 lung adenocarcinoma cell lines were also analyzed by MS to identify enriched proteins in conditioned media in common with proteins with increased levels in plasmas from lung tumor bearing mice. Proteins corresponding to 3744 non-redundant IPIs (International Protein Index) that represented protein products from 2260 unique genes were quantified in one or more experiments. Unsupervised hierarchical clustering of plasma proteins revealed clustering of the four lung cancer models and the two breast cancer models, suggesting that protein signatures in the blood are organ-type specific. Fifty-eight percent of the elevated proteins in plasmas from mice with lung adenocarcinoma were identified in conditioned media of one or more human lung cell lines. A biosignature based on plasma proteins regulated by the Titf1/Nkx2-1 transcription factor was identified in plasmas from mouse models of lung adenocarcinoma. In addition, protein network analysis showed that many proteins whose abundance is altered in the plasma of the lung cancer mouse model engineered to express mutant human EGFR are associated with EGFR. A plasma protein signature that is enriched in proteins associated with neuroendocrine development was also identified in a SCLC model. Exploratory studies in human lung cancer and control plasmas of candidate markers identified in mouse models yielded altered levels in lung cancer plasmas concordant with findings in mouse models. Our studies of mouse models have identified plasma based signature for lung cancer that reflect developmental and signaling pathways applicable to human lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3166. doi:10.1158/1538-7445.AM2011-3166