Journal
CELL REPORTS
Volume 30, Issue 7, Pages 2055-2064Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.01.059
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Funding
- UCLA Medical Scientist Training Program (NIH/NIGMS) [GM008042]
- NIH/NCI NRSA Predoctoral F31 Diversity Fellowship [F31CA239655]
- UCLA Eli AMP
- Edythe Broad Center of Regenerative (BSCRC) Medicine and Stem Cell Research training grant
- T32 National Research Service Award in Tumor Cell Biology [CA009056]
- NIH/NCI [R01CA208303]
- Tobacco Related Disease Research Program (TRDRP) High Impact Pilot Research Award (HIPRA) [26IP-0036]
- TRDRP HIPRA [29IP-0597]
- UCLA Jonsson Comprehensive Cancer Center (JCCC) STOP Cancer Foundation
- UCLA Maximizing Student Development Award (NIH/NIGMS) [R25GM055052]
- NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI grant [UL1TR000124]
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Mechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that beta-catenin phosphorylated at Y489 (p-beta-catenin(Y489)) emerges during human squamous lung cancer progression. This led us to develop a model of airway basal stem cell (ABSC) hyperproliferation by driving Wnt/beta-catenin signaling, resulting in a morphology that resembles premalignant lesions and loss of ciliated cell differentiation. To identify small molecules that could reverse this process, we performed a high-throughput drug screen for inhibitors of Wnt/beta-catenin signaling. Our studies unveil Wnt inhibitor compound 1 (WIC1), which suppresses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity, reduces ABSC proliferation, induces ciliated cell differentiation, and decreases nuclear p-beta-catenin(Y489). Collectively, our work elucidates a dysregulated Wnt/p beta-catenin(Y489) axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/beta-catenin inhibitor that promotes airway homeostasis. WIC1 may therefore serve as a tool compound in regenerative medicine studies with implications for restoring normal airway homeostasis after injury.
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