Journal
CANCER CELL
Volume 36, Issue 2, Pages 156-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.07.002
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Funding
- National Institutes of Health/National Cancer Institute [R01 CA081436-21, R01 CA206267-03, R01 CA140290-05]
- Mayo Clinic Center for Biomedical Discovery Career Development Award
- Edward C. Kendall Fellowship in Biochemistry from Mayo Clinic Graduate School
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We report that mouse LSL-Kras(G12D);Trp53(fl/fl) (KP)-mediated lung adenocarcinoma (LADC) tumorigenesis can proceed through both PKC iota-dependent and PKC iota-independent pathways. The predominant pathway involves PKC iota-dependent transformation of bronchoalveolar stem cells (BASCs). However, KP mice harboring conditional knock out Prkci alleles (KPI mice) develop LADC tumors through PKC iota-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 PKC iota-dependent and PKC iota-independent pathways, resulting in tumors exhibiting distinct oncogenic signaling and pharmacologic vulnerabilities.
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