journal contribution
posted on 2023-03-30, 23:45 authored by Sebastian Marwitz, Sofia Depner, Dmytro Dvornikov, Ruth Merkle, Magdalena Szczygieł, Karin Müller-Decker, Philippe Lucarelli, Marvin Wäsch, Heimo Mairbäurl, Klaus F. Rabe, Christian Kugler, Ekkehard Vollmer, Martin Reck, Swetlana Scheufele, Maren Kröger, Ole Ammerpohl, Reiner Siebert, Torsten Goldmann, Ursula Klingmüller Immunohistochemical analysis of patient material (S1); IHC score for TGF-beta pathway member from matched patient samples (S2); List of TGF-beta regulated genes (S3); List of EMT-related genes (S4); Results of paired t-tests for Microarray (S5); Patient information (S6); List of specific primers used for qRT-PCR gene expression analysis (S7).
Funding
German Center for Lung Research [Deutsches Zentrum für Lungenforschung (DZL)], the German Ministry of Education and Research (BMBF), and in part by the Klara und Werner Kreitz Stiftung
NIH
Helmholtz International Graduate School for Cancer Research at the German Cancer Research Center (DKFZ)
Airway Research Center North (ARCN)
German Center for Lung Research (DZL)
popgen 2.0 network (P2N)
German Ministry for Education and Research
History
ARTICLE ABSTRACT
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 TGFβ 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 TGFβ signaling pathway. Alterations of epithelial-to-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 TGFβ 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 TGFβ-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 TGFβ signaling as a candidate therapeutic target in this setting. Cancer Res; 76(13); 3785–801. ©2016 AACR.
