RESUMO
Mechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that ß-catenin phosphorylated at Y489 (p-ß-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/ß-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/ß-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-ß-cateninY489. Collectively, our work elucidates a dysregulated Wnt/p-ß-cateninY489 axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/ß-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.
Assuntos
Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Proteínas Wnt/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Diferenciação Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Ensaios de Triagem em Larga Escala/métodos , Homeostase/efeitos dos fármacos , Humanos , Pulmão/citologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Células-Tronco/citologia , Células-Tronco/patologia , Transfecção , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismoRESUMO
The paradigm of central nervous system (CNS) drug discovery has mostly relied on traditional approaches of rodent models or cell-based in vitro models. Owing to the issues of species differences between humans and rodents, it is difficult to correlate the robustness of data for neurodevelopmental studies. With advances in the stem-cell field, 3D CNS organoids have been developed and explored owing to their resemblance to the human brain architecture and functions. Further, CNS organoids provide a unique opportunity to mimic the human brain physiology and serve as a modeling tool to study the normal versus pathological brain or the elucidation of mechanisms of neurological disorders. Here, we discuss the recent application of a CNS organoid explored for neurodevelopment disease or a screening tool for CNS drug development.