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We thank Maria Calvo, Lara Sedo, Josep Marimon (CCiTUB), Raquel Bermudo (IDIBAPS), Kyla Driscoll (Eli Lilly), Nuria de-la-Iglesia, Leire Pedrosa, InakiMartinSubero (IDIBAPS), Meritxell Molla, David Sanchez, Cristina Teixido, Daniel Martinez, Josep Ramirez (Hospital Clinic), Alexandre Calon (IMIM), Elena Sancho (IRB), Carolina Francelin (University of Alabama, Birmingham, AL), Natalia Diaz, Alejandro Llorente, Isabel Fabregat, Josep Lluis Carrasco, Daniel Navajas and Ramon Farre (UB), and Cooperative Lung Cancer Group CIBERES-CIBERONC-SEPARBiobanco (Supplementary Materials) for technical support and discussions. This work was supported by grants from the Ministerio de Economia y Competitividad (MINECO/FEDER, UE; PI13/02368 and SAF2016-79527-R to J. Alcaraz; BIO201457716-C2-2-R and BIO2017-89754-C2-2R to C. Fillat; CB16/12/00312 to M. Esteller; FIS PI15/00167 to E. Monso; FIS PI16/01821 to L.M. Montuenga), Fundacio Privada Cellex (to J. Alcaraz), Generalitat de Catalunya (AGAUR SGR 661 and CERCA Programme to J. Alcaraz; SGR 716 to E. Monso), Asociacion Espanola Contra el Cancer (B16-917 to J. Alcaraz; GCB14-2170 to L.M. Montuenga), SEPAR (437 to N. Reguart; PII Oncologia Toracica to E. Monso), and fellowships from Ciencia sem Fronteiras (232704/2014-7 to R. Ikemori) and UB/APIF (to P. Duch).

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Epigenetic SMAD3 repression in tumor-associated fibroblasts impairs fibrosis and response to the antifibrotic drug nintedanib in lung squamous cell carcinoma

Publicated to:Cancer Research. 80 (2): 276-290 - 2020-01-15 80(2), DOI: 10.1158/0008-5472.can-19-0637

Authors: Ikemori, Rafael; Gabasa, Marta; Duch, Paula; Vizoso, Miguel; Bragado, Paloma; Arshakyan, Marselina; Luis, Iuliana-Cristiana; Marin, Albert; Moran, Sebastian; Castro, Manuel; Fuster, Gemma; Gea-Sorli, Sabrina; Jauset, Toni; Soucek, Laura; Montuenga, Luis M; Esteller, Manel; Mons, Eduard; Peinado, Victor Ivo; Gascon, Pere; Fillat, Cristina; Hilberg, Frank; Reguart, Noemi; Alcaraz, Jordi

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Abstract

The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAFs) 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 were associated with increased promoter methylation of the pro-fibrotic TGF-? transcription factor SMAD3 compared to ADC-TAFs, which elicited a compensatory increase in TGF-?1/SMAD2 activation. Consistently, forcing global DNA demethylation of SCC-TAFs with 5-AZA rescued TGF-?1/SMAD3 activation, whereas genetic downregulation of SMAD3 in ADC-TAFs and control fibroblasts increased TGF-?1/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, since 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 ADC patients may be more responsive to antifibrotic drugs targeting their stromal TGF-?1/SMAD3 activation.Copyright ©2019, American Association for Cancer Research.

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