蛋白激酶 Cι 和 Wnt/β-连环蛋白信号通路：Kras/Trp53 驱动的肺腺癌的另一种途径。
Protein Kinase Cι and Wnt/β-Catenin Signaling: Alternative Pathways to Kras/Trp53-Driven Lung Adenocarcinoma.
机构信息
Department of Cancer Biology, Mayo Clinic Florida, 4500 San Pablo Road, Griffin Cancer Research Building, Room 212, Jacksonville, FL 32224, USA.
Department of Pathology, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
出版信息
Cancer Cell. 2019 Aug 12;36(2):156-167.e7. doi: 10.1016/j.ccell.2019.07.002. Epub 2019 Aug 1.
Abstract
We report that mouse LSL-Kras;Trp53 (KP)-mediated lung adenocarcinoma (LADC) tumorigenesis can proceed through both PKCι-dependent and PKCι-independent pathways. The predominant pathway involves PKCι-dependent transformation of bronchoalveolar stem cells (BASCs). However, KP mice harboring conditional knock out Prkci alleles (KPI mice) develop LADC tumors through PKCι-independent transformation of Axin2 alveolar type 2 (AT2) stem cells. Transformed growth of KPI, but not KP, tumors is blocked by Wnt pathway inhibition in vitro and in vivo. Furthermore, a KPI-derived genomic signature predicts sensitivity of human LADC cells to Wnt inhibition, and identifies a distinct subset of primary LADC tumors exhibiting a KPI-like genotype. Thus, LADC can develop through both PKCι-dependent and PKCι-independent pathways, resulting in tumors exhibiting distinct oncogenic signaling and pharmacologic vulnerabilities.
摘要
我们报告称，小鼠 LSL-Kras;Trp53 (KP)介导的肺腺癌 (LADC) 肿瘤发生可以通过 PKCι 依赖和 PKCι 非依赖途径进行。主要途径涉及 PKCι 依赖性的支气管肺泡干细胞 (BASCs) 转化。然而，携带条件敲除 Prkci 等位基因 (KPI 小鼠) 的 KP 小鼠通过 Axin2 肺泡 II 型 (AT2) 干细胞的 PKCι 非依赖性转化发展为 LADC 肿瘤。体外和体内实验表明，Wnt 通路抑制可阻断 KPI 而非 KP 肿瘤的转化生长。此外，KPI 衍生的基因组特征预测了人类 LADC 细胞对 Wnt 抑制的敏感性，并确定了一组具有 KPI 样基因型的独特原发性 LADC 肿瘤亚群。因此，LADC 可以通过 PKCι 依赖和 PKCι 非依赖途径发展，导致肿瘤表现出不同的致癌信号和药物敏感性。
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