Abstract 348: LKB1 deficiency confers lung adenocarcinoma phenotypic plasticity with squamous transdifferentiation potential.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The existence and related mechanisms of phenotypic plasticity and dynamic lineage conversion of lung cancers, as implicated by clinical observation of mixed adenocarcinoma (ADC) and squamous cell carcinoma (SCC) pathologies in adenosquamous cell carcinoma (Ad-SCC), remain as fundamental yet unsolved questions. Here we find that about 13% human lung Ad-SCC harbor genetic alterations of tumor suppressor LKB1. Through lineage tracing experiments and pathological analyses in mouse models of human lung cancer, we further show that LKB1 deficiency confers lung adenocarcinoma phenotypic plasticity to progressively transdifferentiate into squamous cell carcinoma (SCC), via pathologically mixed Ad-SCC as intermediate. Down-regulation of lysyl oxidase (LOX) following reduced hypoxia level in LKB1-deficient lung adenocarcinoma decreases collagen disposition and triggers extracellular matrix remodeling and eventually up-regulates p63 expression, the SCC lineage survival oncogene. Moreover, pharmacological inhibition of Lox enzymatic activity promotes the transdifferentiation, whereas ectopic Lox expression conversely increases collagen deposition and significantly inhibits this process. ADC and SCC show differential response to pharmacological Lox inhibition. Notably, human lung Ad-SCC with LKB1 genetic alterations show pathology-specific patterns of LOX expression and collagen deposition in adenomatous and squamous portions as seen from animal models. These data uncover an essential role and related molecular mechanism of LKB1 deficiency in determining lung adenocarcinoma phenotypic plasticity. Citation Format: Xiangkun Han, Fuming Li, Zhaoyuan Fang, Yijun Gao, Rong Fang, Fei Li, Yihua Sun, Jufeng Xia, Shun Yao, Li Li, Haiquan Chen, Yingyong Hou, Xinyuan Liu, Hongbin Ji. LKB1 deficiency confers lung adenocarcinoma phenotypic plasticity with squamous transdifferentiation potential. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 348. doi:10.1158/1538-7445.AM2013-348