LSC - 2017 - Deregulated SOX2 drives a migratory signature in a novel organotypic model of bronchial dysplasia

The molecular pathogenesis of squamous lung cancer is poorly understood – addressing this is a critical first step in improving early detection and treatment of this devastating disease. SOX2 amplification and overexpression is one of the most frequent genetic alterations in SQC (up to 90%). Although, it has been shown that deregulated SOX2 is an early and consistent event in squamous carcinogenesis, little is known about its downstream effects in early disease. We used a novel organotypic model of bronchial dysplasia to interrogate downstream effectors of SOX2 deregulation.In the novel organotypic culture system, SOX2 overexpression, in co-operation with loss of p53 was sufficient to initiate bronchial dysplasia. RNA-seq analyses showed that SOX2 activated downstream targets involved in multiple pro-tumorigenic signatures including cell proliferation, epithelial mesenchymal transition and migration and metastasis. SERPINI1 was one of the most significantly upregulated genes. SERPINI1 has been described to promote brain metastasis from lung and breast cancer; it is upregulated in over 50% of the patients and tends to be co-amplified with SOX2. QPCR and WB analyses validated RNA-seq findings and, ChIP-PCR revealed that SERPINI1 is a SOX2 direct target in the model. Finally, immunohistochemical staining in preinvasive and invasive squamous lung lesions showed marked cytoplasmic expression of SERPINI1 and co-localisation with SOX2 expression.To summarise, we have performed...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Lung Cancer Source Type: research