Pten and p53 Loss in the Mouse Lung Causes Adenocarcinoma and Sarcomatoid Carcinoma.

Abstract

Simple SummaryLung cancer is the world leading cause of cancer death. Therefore, a better understanding of the disease is needed to improve patient survival. In this work, we have deleted the tumor suppressor genes Pten and Trp53 in adult mouse lungs to analyze its impact on tumor formation. Double mutant mice develop Adenocarcinoma and Pulmonary Sarcomatoid Carcinoma, two different types of Non-Small Cell Carcinoma whose biological relationships are a matter of debate. The former is very common, with various models described and some therapeutic options. The latter is very rare with very poor prognosis, no effective treatment and lack of models reported so far. Interestingly, this study reports the first mouse model of pulmonary sarcomatoid carcinoma available for preclinical research.Lung cancer remains the leading cause of cancer deaths worldwide. Among the Non-Small Cell Carcinoma (NSCLC) category, Adenocarcinoma (ADC) represents the most common type, with different reported driver mutations, a bunch of models described and therapeutic options. Meanwhile, Pulmonary Sarcomatoid Carcinoma (PSC) is one of the rarest, with very poor outcomes, scarce availability of patient material, no effective therapies and no models available for preclinical research. Here, we describe that the 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 after 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 the mouse PSC, providing a link between both tumor types and the human ADC.