Aberrant epithelial polarity cues drive the development of precancerous airway lesions
Menée à l'aide notamment de cellules épithéliales bronchiques humaines et d'un modèle murin, cette étude met en évidence un mécanisme par lequel des perturbations de la polarité des cellules épithéliales favorisent le développement de lésions précancéreuses au niveau des voies respiratoires
This study demonstrates that damage to lung epithelial architecture induces aberrant cellular signals that promote the development of precancerous airway lesions. These signals are mediated by the uncontrolled activation of the transcriptional effectors YAP and TAZ, which drive the expression of the growth factor NRG1 and the consequent activation of the ERBB receptors. Genetic deletion of YAP/TAZ or pharmacological inhibition of ERBB receptors prevents and treats precancer airway lesion development following epithelial damage, offering important knowledge that may guide therapeutic strategies for intercepting the development of squamous lung cancers.Molecular events that drive the development of precancerous lesions in the bronchial epithelium, which are precursors of lung squamous cell carcinoma (LUSC), are poorly understood. We demonstrate that disruption of epithelial cellular polarity, via the conditional deletion of the apical determinant Crumbs3 (Crb3), initiates and sustains precancerous airway pathology. The loss of Crb3 in adult luminal airway epithelium promotes the uncontrolled activation of the transcriptional regulators YAP and TAZ, which stimulate intrinsic signals that promote epithelial cell plasticity and paracrine signals that induce basal-like cell growth. We show that aberrant polarity and YAP/TAZ-regulated gene expression associates with human bronchial precancer pathology and disease progression. Analyses of YAP/TAZ-regulated genes further identified the ERBB receptor ligand Neuregulin-1 (NRG1) as a key transcriptional target and therapeutic targeting of ERBB receptors as a means of preventing and treating precancerous cell growth. Our observations offer important molecular insight into the etiology of LUSC and provides directions for potential interception strategies of lung cancer.RNA-sequencing data have been deposited in National Center for Biotechnology Information Gene Expression Omnibus (GSE133493).