1. Epigenetic SMAD3 Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma.
- Author
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Ikemori R, Gabasa M, Duch P, Vizoso M, Bragado P, Arshakyan M, Luis IC, Marín A, Morán S, Castro M, Fuster G, Gea-Sorli S, Jauset T, Soucek L, Montuenga LM, Esteller M, Monsó E, Peinado VI, Gascon P, Fillat C, Hilberg F, Reguart N, and Alcaraz J
- Subjects
- Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology, Adenocarcinoma of Lung surgery, Aged, Aged, 80 and over, Animals, Cancer-Associated Fibroblasts drug effects, Cancer-Associated Fibroblasts pathology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung surgery, Cohort Studies, DNA Methylation genetics, Epigenetic Repression, Female, Fibrosis, Gene Expression Regulation, Neoplastic, Humans, Indoles therapeutic use, Lung cytology, Lung drug effects, Lung pathology, Lung surgery, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms surgery, Male, Mice, Middle Aged, Pneumonectomy, Promoter Regions, Genetic genetics, Smad2 Protein genetics, Smad2 Protein metabolism, Smad3 Protein metabolism, Tissue Array Analysis, Xenograft Model Antitumor Assays, Adenocarcinoma of Lung drug therapy, Carcinoma, Non-Small-Cell Lung drug therapy, Drug Resistance, Neoplasm genetics, Indoles pharmacology, Lung Neoplasms drug therapy, Smad3 Protein genetics
- Abstract
The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAF) is drawing increased therapeutic attention. Intriguingly, a trial with the antifibrotic drug nintedanib in non-small cell lung cancer reported clinical benefits in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC), even though the stroma is fibrotic in both histotypes. Likewise, we reported that nintedanib inhibited the tumor-promoting fibrotic phenotype of TAFs selectively in ADC. Here we show that tumor fibrosis is actually higher in ADC-TAFs than SCC-TAFs in vitro and patient samples. Mechanistically, the reduced fibrosis and nintedanib response of SCC-TAFs was associated with increased promoter methylation of the profibrotic TGFβ transcription factor SMAD3 compared with ADC-TAFs, which elicited a compensatory increase in TGFβ1/SMAD2 activation. Consistently, forcing global DNA demethylation of SCC-TAFs with 5-AZA rescued TGFβ1/SMAD3 activation, whereas genetic downregulation of SMAD3 in ADC-TAFs and control fibroblasts increased TGFβ1/SMAD2 activation, and reduced their fibrotic phenotype and antitumor responses to nintedanib in vitro and in vivo . Our results also support that smoking and/or the anatomic location of SCC in the proximal airways, which are more exposed to cigarette smoke particles, may prime SCC-TAFs to stronger SMAD3 epigenetic repression, because cigarette smoke condensate selectively increased SMAD3 promoter methylation. Our results unveil that the histotype-specific regulation of tumor fibrosis in lung cancer is mediated through differential SMAD3 promoter methylation in TAFs and provide new mechanistic insights on the selective poor response of SCC-TAFs to nintedanib. Moreover, our findings support that patients with ADC may be more responsive to antifibrotic drugs targeting their stromal TGFβ1/SMAD3 activation. SIGNIFICANCE: This study implicates the selective epigenetic repression of SMAD3 in SCC-TAFs in the clinical failure of nintedanib in SCC and supports that patients with ADC may benefit from antifibrotic drugs targeting stromal TGFβ1/SMAD3., (©2019 American Association for Cancer Research.)
- Published
- 2020
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