TY - JOUR
T1 - Protein Kinase Cι and Wnt/β-Catenin Signaling
T2 - Alternative Pathways to Kras/Trp53-Driven Lung Adenocarcinoma
AU - Yin, Ning
AU - Liu, Yi
AU - Khoor, Andras
AU - Wang, Xue
AU - Thompson, E. Aubrey
AU - Leitges, Michael
AU - Justilien, Verline
AU - Weems, Capella
AU - Murray, Nicole R.
AU - Fields, Alan P.
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/8/12
Y1 - 2019/8/12
N2 - 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.
AB - 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.
KW - Kras/Trp53 transformation
KW - Wnt signaling
KW - alveolar type 2 cells
KW - bronchoalveolar stem cells
KW - lung adenocarcinoma molecular subtypes
KW - lung cancer
KW - protein kinase Cι signaling
KW - therapeutic vulnerability
UR - http://www.scopus.com/inward/record.url?scp=85071353089&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071353089&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2019.07.002
DO - 10.1016/j.ccell.2019.07.002
M3 - Article
C2 - 31378680
AN - SCOPUS:85071353089
SN - 1535-6108
VL - 36
SP - 156-167.e7
JO - Cancer cell
JF - Cancer cell
IS - 2
ER -