| Literature DB >> 31378680 |
Ning Yin1, Yi Liu1, Andras Khoor2, Xue Wang3, E Aubrey Thompson1, Michael Leitges4, Verline Justilien1, Capella Weems1, Nicole R Murray1, Alan P Fields5.
Abstract
We report that mouse LSL-KrasG12D;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.Entities:
Keywords: Kras/Trp53 transformation; Wnt signaling; alveolar type 2 cells; bronchoalveolar stem cells; lung adenocarcinoma molecular subtypes; lung cancer; protein kinase Cι signaling; therapeutic vulnerability
Year: 2019 PMID： 31378680 PMCID： PMC6693680 DOI： 10.1016/j.ccell.2019.07.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743