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

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

Research output: Contribution to journalArticle

7 Scopus citations

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. Yin et al. discover that KrasG12D;Trp53−/− (KP)-driven mouse lung adenocarcinomas (LADCs) are phenotypically different from KP LADCs without PKCι (KPI) expression. A KPI-derived genomic signature identifies KPI-like human LADCs and predicts susceptibility to Wnt inhibitors.

Original languageEnglish (US)
Pages (from-to)156-167.e7
JournalCancer cell
Volume36
Issue number2
DOIs
StatePublished - Aug 12 2019

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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