Pten and p53 loss in the mouse lung causes adenocarcinoma and sarcomatoid carcinoma

Here we describe novel murine models of pulmonary adenocarcinoma (ADC) and sarcomatoid carcinoma (PSC) driven by the loss of two tumor suppressors: deletion of Trp53 and Pten. Combined deletion of Pten and Trp53 in the lungs of adult conditional mice leads to the development of both ADC and PSC irrespective of the lung targeted cell type or naphthalene induced airway epithelial regeneration. Although this model shows long latency periods and incomplete penetrance for tumor development, it is the first PSC mouse model reported so far, and sheds light on the relationships between ADC and PSC and their cells of origin. Moreover, human ADC show strong transcriptomic similarities to mouse PSC, providing a link between these tumor types and human ADC. Ablation of Trp53 and Pten in pulmonary cells was achieved by intratracheal administration of purified Ad5-CMVcre or Ad5-K5cre (Du Page et al, 2009) to Trp53F/F; PtenF/F 8–10 week old mice. Mice were sacrificed at different time points after the Ad5-cre infection and tumors processed for whole transcriptome analysis. As control animals, Trp53F/F; PtenF/F littermates were used. Gene expression was studied in normal mouse lung and in lung tumours from Trp53F/F; PtenF/F mice treated by intratracheal administration of Ad5-CMVcre or Ad5-K5cre to ablate Trp53 and Pten in pulmonary cells. Some mice were pretreated with a single dose of naphthalene delivered by intraperitoneal injection (200mg naphthalene per kg body weight) three days before intratracheal administration of adenovirus.