Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Harvard Medical School, Boston, MA, USA.
Commun Biol. 2021 Apr 14;4(1):370. doi: 10.1038/s42003-021-01897-6.
Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.
肺癌是癌症死亡的主要原因。肿瘤异质性阻碍了靶向治疗的发展，本研究通过单细胞 RNA 测序对侵袭性人类腺癌（携带 Kras 突变）和可比的小鼠模型进行了剖析。我们鉴定了一种肿瘤特异性的、与突变 KRAS 相关的亚群，在人类和小鼠肺癌中均保守。我们之前报道了癌基因 BMI-1 在腺癌中的关键作用。因此，我们研究了在我们的小鼠模型中影响 BMI-1 活性的体内 PTC596 治疗的效果。治疗后，MRI 分析显示肿瘤体积减小，而单细胞转录组学同时检测到与突变 KRAS 相关的亚群几乎完全消融，表明存在一种可通过药理学靶向治疗的肿瘤相关亚群。因此，我们的研究结果为开发针对 KRAS 突变型腺癌的靶向治疗提供了希望。
Zotero 插件
