USP13 Drives Lung Squamous Cell Carcinoma via Switching Lung Club Cell Lineage Plasticity

Lung squamous cell carcinoma (LUSC) is associated with high mortality and limited targeted therapies. USP13 is one of the most amplified genes in LUSC, and yet its role in lung cancer is largely unknown. Here, we establish a novel mouse model of LUSC by overexpressing USP13 in KrasG12D/+; Trp53flox/flox background (KPU). KPU model faithfully recapitulates the key pathohistological, molecular features, and cellular pathways of human LUSC. We found that USP13 altered lineage-determining factors such as NKX2-1 and SOX2 in club cells (CC10+) of the airway and reinforced the fate of club cells to squamous carcinoma development. We also showed a strong molecular association between USP13 and MYC, leading to the upregulation of squamous programs in murine and human lung cancer cells. Collectively, our data demonstrate USP13 as a molecular driver of lineage plasticity in club cells and provide mechanistic insight that may have potential implications for the treatment of NSCLC. To analyze the function of USP13 in lung cancer development, we established lung cancers from KP and KPU mice by intratracheal injection of Ad5-CMV-Cre virus