Abstract:
Lung squamous cell carcinoma (LUSC) is associated with high mortality and limited targeted therapies. USP13 is one of the most amplified genes in LUSC, yet its role in lung cancer is largely unknown. Here, we established a novel mouse model of LUSC by overexpressing USP13 on KrasG12D/+; Trp53flox/flox background (KPU). KPU-driven lung squamous tumors faithfully recapitulate 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 of the airway and reinforced the fate of club cells to squamous carcinoma development. We showed a strong molecular association between USP13 and c-MYC, leading to the upregulation of squamous programs in murine and human lung cancer cells. Collectively, our data demonstrate that USP13 is a molecular driver of lineage plasticity in club cells and provide mechanistic insight that may have potential implications for the treatment of LUSC.
摘要:
肺鳞状细胞癌(LUSC)与高死亡率和有限的靶向治疗相关。USP13是LUSC中扩增最多的基因之一,然而,它在肺癌中的作用在很大程度上是未知的。这里,我们通过在KrasG12D/+;Trp53flox/flox背景(KPU)上过度表达USP13,建立了一种新型的LUSC小鼠模型。KPU驱动的肺鳞状肿瘤忠实地概括了关键的病理组织学,分子特征,和人类LUSC的细胞途径。我们发现USP13改变了气道俱乐部细胞中的谱系决定因子,例如NKX2-1和SOX2,并增强了俱乐部细胞向鳞状细胞发展的命运。我们显示了USP13和c-MYC之间的强分子关联,导致鼠和人肺癌细胞鳞状细胞程序的上调。总的来说,我们的数据表明,USP13是俱乐部细胞谱系可塑性的分子驱动因素,并提供了可能对LUSC治疗有潜在影响的机制见解.