Downregulation of the TGFβ Pseudoreceptor BAMBI in Non-Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGF beta elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGF beta signaling pathway. Alterations of epithelialto- mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared with tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGF beta pathway components were detected in NSCLC samples compared with tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGF beta-induced EMT, migration, and invasion in vitro, along with reduced tumor burden and tumor growth in vivo. In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGF beta signaling as a candidate therapeutic target in this setting. (C) 2016 AACR.