High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis
Cody J. Aros,
Manash K. Paul,
Carla J. Pantoja,
Bharti Bisht,
Luisa K. Meneses,
Preethi Vijayaraj,
Jenna M. Sandlin,
Bryan France,
Jonathan A. Tse,
Michelle W. Chen,
David W. Shia,
Tammy M. Rickabaugh,
Robert Damoiseaux,
Brigitte N. Gomperts
Affiliations
Cody J. Aros
UCLA Department of Molecular Biology Interdepartmental Program, UCLA, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Manash K. Paul
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Carla J. Pantoja
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Bharti Bisht
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Luisa K. Meneses
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Preethi Vijayaraj
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA
Jenna M. Sandlin
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Bryan France
California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA
Jonathan A. Tse
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Michelle W. Chen
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
David W. Shia
UCLA Department of Molecular Biology Interdepartmental Program, UCLA, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Tammy M. Rickabaugh
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Robert Damoiseaux
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; UCLA Department of Molecular & Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA
Brigitte N. Gomperts
UCLA Medical Scientist Training Program, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA; Corresponding author
Summary: Mechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that β-catenin phosphorylated at Y489 (p-β-cateninY489) emerges during human squamous lung cancer progression. This led us to develop a model of airway basal stem cell (ABSC) hyperproliferation by driving Wnt/β-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/β-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-β-cateninY489. Collectively, our work elucidates a dysregulated Wnt/p-β-cateninY489 axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/β-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. : Aros et al. unveil a dysregulated Wnt/β-catenin signaling axis in lung premalignancy that can be modeled in vitro. They leverage this knowledge to conduct a drug screen and identify a small-molecule inhibitor of Wnt/β-catenin signaling that restores airway epithelial homeostasis. Keywords: homeostasis, drug screen, Wnt, beta-catenin, lung, premalignancy, airway stem cell
