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Title: Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts
Author: Vizoso, Miguel
Puig, Marta
Carmona, F. Javier
Maqueda, María
Velásquez Vacca, Adriana
Gómez, Antonio
Labernadie, Anna
Lugo, Roberto
Gabasa Ferràndez, Marta
Rigat Brugarolas, Luis Guillermo
Trepat Guixer, Xavier
Ramírez, Josep
Moran, Sebastian
Vidal, Enrique
Reguart, Noemí
Perera Lluna, Alexandre
Esteller, Manel
Alcaraz Casademunt, Jordi
Keywords: ADN
Càncer de pulmó
Marcadors tumorals
Lung cancer
Tumor markers
Issue Date: Dec-2015
Publisher: Oxford University Press
Abstract: Epigenetic changes through altered DNA methylation have been implicated in critical aspects of tumor progression, and have been extensively studied in a variety of cancer types. In contrast, our current knowledge of the aberrant genomic DNA methylation in tumor-associated fibroblasts (TAFs) or other stromal cells that act as critical coconspirators of tumor progression is very scarce. To address this gap of knowledge, we conducted genome-wide DNA methylation profiling on lung TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer patients using the HumanMethylation450 microarray. We found widespread DNA hypomethylation concomitant with focal gain of DNA methylation in TAFs compared to CFs. The aberrant DNA methylation landscape of TAFs had a global impact on gene expression and a selective impact on the TGF-β pathway. The latter included promoter hypermethylation-associated SMAD3 silencing, which was associated with hyperresponsiveness to exogenous TGF-β1 in terms of contractility and extracellular matrix deposition. In turn, activation of CFs with exogenous TGF-β1 partially mimicked the epigenetic alterations observed in TAFs, suggesting that TGF-β1 may be necessary but not sufficient to elicit such alterations. Moreover, integrated pathway-enrichment analyses of the DNA methylation alterations revealed that a fraction of TAFs may be bone marrow-derived fibrocytes. Finally, survival analyses using DNA methylation and gene expression datasets identified aberrant DNA methylation on the EDARADD promoter sequence as a prognostic factor in non-small cell lung cancer patients. Our findings shed light on the unique origin and molecular alterations underlying the aberrant phenotype of lung TAFs, and identify a stromal biomarker with potential clinical relevance.
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It is part of: Carcinogenesis, 2015, vol. 36, num. 12, p. 1453-1463
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ISSN: 0143-3334
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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