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 - Funding Information:
We thank Ms. Kayla Lewis and Dr. Lee Jamieson for technical assistance, Ms. Brandy Edenfield and the Mayo Clinic Cancer Biology Histology Facility for processing tumor tissues for analysis, The Mayo Clinic Sequencing Facility for RNA-seq runs, and Dr. Laura J. Tuffin-Lewis for assistance with flow-cytometric analysis. We also acknowledge members of the Fields laboratory for critical feedback on the manuscript. This work was supported by grants from the National Institutes of Health /National Cancer Institute ( R01 CA081436–21 and R01 CA206267-03 to A.P.F.; R01 CA140290-05 to N.R.M.). A.P.F . is the Monica Flynn Jacoby Professor of Cancer Research, an endowment fund that provides partial support for the investigator's research program. V.J. is a recipient of a Mayo Clinic Center for Biomedical Discovery Career Development Award. N.Y. and Y.L. are recipients of the Edward C. Kendall Fellowship in Biochemistry from the Mayo Clinic Graduate School.
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
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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 -