High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis

Details

• Alternative Title:
  Cell Rep
• Personal Author:
  Aros, Cody J. ; Paul, Manash K. ; Pantoja, Carla J. ; Bisht, Bharti ; Meneses, Luisa K. ; Vijayaraj, Preethi ; Sandlin, Jenna M. ; France, Bryan ; Tse, Jonathan A. ; Chen, Michelle W. ; Shia, David W. ; Rickabaugh, Tammy M. ; Damoiseaux, Robert ; Gomperts, Brigitte N.
• Description:
  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-catenin|) 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-catenin|. Collectively, our work elucidates a dysregulated Wnt/p-β-catenin| 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.
• Subjects:
  Animals Beta Catenin Bronchi Cell Differentiation Drug Evaluation, Preclinical Female High-Throughput Screening Assays Homeostasis Humans Lung Male Mice Mice, Inbred C57BL Precancerous Conditions Small Molecule Libraries Stem Cells Transfection Wnt Proteins Wnt Signaling Pathway

  More +
• Source:
  Cell Rep. 30(7):2055-2064.e5
• Pubmed ID:
  32075752
• Pubmed Central ID:
  PMC7050206
• Document Type:
  Journal Article
• Funding:
  T32 GM008042/GM/NIGMS NIH HHSUnited States/ ; R01 CA208303/CA/NCI NIH HHSUnited States/ ; UL1 TR000124/TR/NCATS NIH HHSUnited States/ ; R25 GM055052/GM/NIGMS NIH HHSUnited States/ ; P30 CA016042/CA/NCI NIH HHSUnited States/ ; F31 CA239655/CA/NCI NIH HHSUnited States/ ; T34 GM008563/GM/NIGMS NIH HHSUnited States/ ; T32 CA009056/CA/NCI NIH HHSUnited States/ ; U66 IP000597/IP/NCIRD CDC HHSUnited States/
• Volume:
  30
• Issue:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0678c46311aa862a8db09dcb0e9363116b57089933d65e74e1178d59981b56a9
• Download URL:
  https://stacks.cdc.gov/view/cdc/154728/cdc_154728_DS1.pdf
• File Type:
  [PDF - 2.42 MB ]