Lysyl oxidase inhibition drives the transdifferentiation from lung adenocarcinoma to squamous cell carcinoma in mice

AbstractLKB1is frequently mutated in human non-small cell lung cancer (NSCLC) andLkb1deletion 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 inKrasG12D/Trp53L/Lmouse model, which is known to produce lung ADC only, triggers the ADC-to-SCC transdifferentiation independent ofLKB1status. 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 ofLKB1inactivation status.