美国梅奥诊所Alan P. Fields课题组发现蛋白激酶Cι和Wnt /β-Catenin是Kras/Trp53驱动的肺腺癌发生的替代途径。相关论文于2019年8月12日发表在《癌细胞》上。

研究人员发现，LSL-Kras^G12D;Trp53^fl/fl（KP）小鼠的肺腺癌（LADC）肿瘤发生，可以通过PKCι依赖和PKCι非依赖途径进行。发生的主要途径涉及支气管肺泡干细胞（BASC）的PKCι依赖性转化。然而，携带有条件性敲除Prkci等位基因的KP小鼠（即KPI小鼠）通过Axin2 阳性2型肺泡（AT2）干细胞的PKCι非依赖性转化产生LADC肿瘤。KPI肿瘤的转化生长在体外和体内均可被Wnt途径抑制所阻断，但KP肿瘤不行。此外，KPI来源的基因组特征能够预测人LADC细胞对Wnt抑制的敏感性，并鉴定了表现出KPI样基因型的原发性LADC肿瘤的不同亚群。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理弱点。

附：英文原文

Title: Protein Kinase Cι and Wnt/β-Catenin Signaling: Alternative Pathways to Kras/Trp53-Driven Lung Adenocarcinoma

Author: Ning Yin, Yi Liu, Andras Khoor, Xue Wang, E. Aubrey Thompson, Michael Leitges, Verline Justilien, Capella Weems, Nicole R. Murray, Alan P. Fields

Issue&Volume: Volume 36 Issue 2

Abstract: We report that mouse LSL -Kras G12D; Trp53fl/fl (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.

DOI: https://doi.org/10.1016/j.ccell.2019.07.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30329-0