Abstract 2308: The role of LKB1 in development of lung squamous cell carcinoma in mice

Abstract

Abstract LKB1 is frequently dysregulated in human lung cancer and has been shown to be one of the critical genes controlling the development of lung squamous cell carcinoma (SCC) in mice1,2. However, it's unclear that the contribution of LKB1 in the development of lung SCC in mice. Here we took advantage of our new enhanced Cre (CCSPiCre) to efficiently deplete Lkb1 in the mouse airway epithelial cells. Although ablation of Lkb1 failed to show any discernable morphological changes, microarray analysis revealed 503 genes and 202 LincRNAs were significantly altered after single ablation of Lkb1. Ingenuity Pathway Analysis (IPA) showed that LXR/RXR activation and inflammatory pathways were significantly dysregulated by ablation of Lkb1. Using the CCSPiCre mouse, we ablated Pten in addition to Lkb1. As previously reported by Xu and coworkers who used Adenoviral delivery of Cre recombinase to achieve Lkb1 and Pten ablation2, the resulting phenotype was SCC while much rapider tumor initiation age, higher mouse metastasis ratio and a worse mortality were observed in this efficient mouse model. Analysis of the tumor development showed progression from mucous cell hyperplasia of the large airways to a papillary transition stage, then to the SCC phenotype. Mice with airway specific loss of Lkb1 and only one allele of Pten (CCSPiCrePtenf/+Lkb1f/f) showed slower tumor progression with the strong metastasis ability to multiple organs, such as liver, uterus, intestine and spleen. Comparison of the microarrays of CCSPiCrePtenf/f and CCSPiCrePtenf/fLkb1f/f in the pretumor stage showed 1463 genes and 339 LincRNAs were significantly altered. Again the major altered pathways were inflammatory and cholesterol biosynthesis. Using this model the developmental progression of lung SCC and the contribution of LKB1 to lung SCC progression were determined.