Abstract
LKB1 is frequently mutated in human non-small cell lung cancer (NSCLC) and Lkb1 deletion in mice triggered the lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC) transdifferentiation (AST) through lysyl oxidase (LOX)-dependent extracellular matrix remodeling. Here we show that pharmacological inhibition of lysyl oxidase in KrasG12D/Trp53L/L mouse model, which is known to produce lung ADC only, triggers the ADC-to-SCC transdifferentiation independent of LKB1 status. Treatments of two different inhibitors of lysyl oxidase decrease collagen deposition and promote redox accumulation, and eventually trigger the AST. Importantly, these transited SCC show strong resistance to lysyl oxidase inhibition in stark contrast to ADC. Collectively, these findings establish a new AST mouse model independent of LKB1 inactivation status.
Footnotes
Grant Support This work was supported by the National Basic Research Program of China (2017YFA0505500), the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDB19000000, the National Natural Science Foundation of China 81430066, 91731314, 31621003), Science and Technology Commission of Shanghai Municipality (15XD1504000) and China Postdoctoral Science Foundation (2015M581673).