2 research outputs found
Epigenetic SMAD3 Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma
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 TGFb transcription factor SMAD3
compared with ADC-TAFs, which elicited a compensatory increase
in TGFb1/SMAD2 activation. Consistently, forcing global DNA
demethylation of SCC-TAFs with 5-AZA rescued TGFb1/SMAD3
activation, whereas genetic downregulation of SMAD3 in ADCTAFs and control fibroblasts increased TGFb1/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 SCCTAFs to nintedanib. Moreover, our findings support that patients
with ADC may be more responsive to antifibrotic drugs targeting
their stromal TGFb1/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 TGFb1/
SMAD3
Epigenetic SMAD3 Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma
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 TGFb transcription factor SMAD3
compared with ADC-TAFs, which elicited a compensatory increase
in TGFb1/SMAD2 activation. Consistently, forcing global DNA
demethylation of SCC-TAFs with 5-AZA rescued TGFb1/SMAD3
activation, whereas genetic downregulation of SMAD3 in ADCTAFs and control fibroblasts increased TGFb1/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 SCCTAFs to nintedanib. Moreover, our findings support that patients
with ADC may be more responsive to antifibrotic drugs targeting
their stromal TGFb1/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 TGFb1/
SMAD3