Tumor heterogeneity and cisplatin resistance are major causes of tumor relapse and poor survival. Here, we show that in lung cancer, interaction between paxillin (PXN) and integrin β4 (ITGB4), components of the focal adhesion (FA) complex, contributes to cisplatin resistance. Knocking down PXN and ITGB4 attenuated cell growth and improved cisplatin sensitivity, both in 2D and 3D cultures. PXN and ITGB4 independently regulated expression of several genes. In addition, they also regulated expression of common genes including USP1 and VDAC1, which are required for maintaining genomic stability and mitochondrial function, respectively. Mathematical modeling suggested that bistability could lead to stochastic phenotypic switching between cisplatin-sensitive and resistant states in these cells. Consistently, purified subpopulations of sensitive and resistant cells re-created the mixed parental population when cultured separately. Altogether, these data point to an unexpected role of the FA complex in cisplatin resistance and highlight a novel non-genetic mechanism.

肿瘤异质性和顺铂耐药是肿瘤复发和生存率低的主要原因。在这里，我们发现在肺癌中，桩蛋白 (PXN) 和整合素 β4 (ITGB4)（黏着斑 (FA) 复合物的组成部分）之间的相互作用导致顺铂耐药。在 2D 和 3D 培养物中，敲除 PXN 和 ITGB4 可减弱细胞生长并提高顺铂敏感性。PXN 和 ITGB4 独立调节多个基因的表达。此外，它们还调节包括 USP1 和 VDAC1 在内的常见基因的表达，这些基因分别是维持基因组稳定性和线粒体功能所必需的。数学模型表明，双稳定性可能导致这些细胞中顺铂敏感状态和耐药状态之间的随机表型转换。一致地，纯化的敏感细胞和耐药细胞亚群在单独培养时重新产生了混合亲本群体。总而言之，这些数据表明 FA 复合物在顺铂耐药性中发挥着意想不到的作用，并强调了一种新的非遗传机制。