Novel Molecular and Phenotypic Insights into Congenital Lung Malformations

• Published in: American journal of respiratory and critical care medicine Vol. 197; no. 10; pp. 1328 - 1339
• Main Authors: Swarr, Daniel T, Peranteau, William H, Pogoriler, Jennifer, Frank, David B, Adzick, N Scott, Hedrick, Holly L, Morley, Mike, Zhou, Su, Morrisey, Edward E
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 15-05-2018
• Subjects: Birth defects; Cystic Adenomatoid Malformation of Lung, Congenital - genetics; Cystic Adenomatoid Malformation of Lung, Congenital - surgery; Cysts; Etiology; Female; Gene expression; Genetic Predisposition to Disease; Growth factors; Histology; Humans; Infant; Infant, Newborn; Kinases; Lung - physiopathology; Male; Morphogenesis; Mutation; Original; Pathogenesis; Pennsylvania; Phenotype; Respiratory System Abnormalities - genetics; Respiratory System Abnormalities - surgery; Pennsylvania; United States > US; congenital cystic adenomatoid malformation of the lung; congenital pulmonary airway malformation; branching morphogenesis; structural birth defects; lung development
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201706-1243OC

Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected.
To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions.
Clinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3).
Congenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions.
This study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K-AKT-mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.