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Sabrina Gea-Sorli
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OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)
- Event: WCLC 2019
- Type: Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Luis M Montuenga, Julie George
- Coordinates: 9/09/2019, 11:00 - 12:30, Interlaken (1988)
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OA08.07 - Aberrant Epigenetic SMAD3 Signaling in Tumor-Associated Fibroblasts Modulates Fibrosis and Response to Nintedanib in NSCLC (Now Available) (ID 1972)
11:00 - 12:30 | Author(s): Sabrina Gea-Sorli
- Abstract
- Presentation
Background
Tumor-associated fibroblasts (TAFs) exhibit a fibrotic phenotype in non-small cell lung cancer (NSCLC) that has beeen associated with critical steps of cancer progression. Paradoxically, we reported that the profibrotic TGF-β transcription factor SMAD3 was epigenetically downregulated through promoter hypermethylation in TAFs from NSCLC patients compared to patient-matched control fibroblasts. In addition, we reported that the antifibrotic drug nintedanib elicited a stronger inhibition of the fibrotic phenotype and its tumor-promoting effects in TAFs from adenocarcinoma (ADC) patients compared to squamous cell carcinoma (SCC) patients upon TGF-β1 stimulation in vitro, which was consistent with the selective therapeutic response to nintedanib observed in a clinical trial in ADC (but not SCC) patients. These previous results support the hypothesis that TGF-β1 signaling may be altered in lung TAFs according to their histologic subtype.
Method
In this study we tested our working hypothesis by determining the expression and activity of SMAD3 and its closely related homologue SMAD2 in patient-derived TAFs and paired control fibroblasts, and by dissecting their potential contribution to the differential therapeutic responses to nintedanib observed in ADC and SCC using in vitro and in vivo preclinical models.
Result
In vitro studies revealed a marked SMAD3 epigenetic repression through promoter hypermethylation, a low pSMAD3/pSMAD2 ratio and a limited fibrotic phenotype selectively in SCC-TAFs. In contrast, ADC-TAFs overexpressed a panel of fibrotic markers upon TGF-β1 stimulation concomitantly with a high pSMAD3/pSMAD2 ratio and a limited SMAD3 promoter methylation. Histologic analysis of a large patient cohort (112 ADC, 96 SCC) confirmed that the extent of fibrosis is larger in ADC than SCC patients. In addition, knocking-down SMAD3 in ADC-TAFs was sufficient to reduce the antifibrotic and antigrowth effects of nintedanib in vitro and in tumor xenografts in vivo. On the other hand, long-term exposure of pulmonary fibroblasts to cigarette smoke condensate was sufficient to hypermethylate the SMAD3 promoter. Since SCC and ADC tumors typically arise in the upper airways and distal pulmonary sites, respectively, it is conceivable that fibroblasts might be more exposed to the smoking epigenetic effects on SMAD3 in SCC.
Conclusion
We report for the first time that tumor fibrosis is higher in ADC than SCC patients, in association with a selective therapeutic response to the antifibrotic drug nintedanib in the former, and identify the subtype-specific extent of SMAD3 epigenetic repression in TAFs and the subsequent aberrant SMAD3/SMAD2 imbalance as major regulatory mechanisms of tumor fibrosis and response to nintedanib in NSCLC.
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