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Frank Hilberg
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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): Frank Hilberg
- 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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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-02 - Nintedanib Selectively Inhibits Angiogenesis Induced by the Conditioned Medium of Lung Adenocarcinoma TAFs in Vitro (ID 2193)
09:45 - 18:00 | Author(s): Frank Hilberg
- Abstract
Background
Nintedanib is an antifibrotic and antiangiogenic drug that was clinically approved to treat EGFR-wild-type lung adenocarcinoma (ADC) patients based on the positive therapeutic results elicited in combination with docetaxel in the LUME-Lung1 clinical trial in ADC but not in squamous cell carcinoma (SCC) patients. However, the mechanisms underlying the selective therapeutic effects of nintedanib in ADC remain poorly understood. Tumor-associated fibroblasts (TAFs) are the most abundant stromal cell type and have been implicated in all steps of tumor progression, including growth, angiogenesis, invasion, metastasis and resistance to therapies. Of note, we recently reported that nintedanib elicits larger antifibrotic effects in ADC-TAFs compared to SCC-TAFs in vitro. However, the antiangiogenic effects of nintedanib in TAFs remain unknown.
Method
ADC-TAFs and SCC-TAFs were activated with TGF-β1 in the presence or absence of nintedanib, and the corresponding conditioned medium was used to stimulate endothelial cells (HUVECs and HMVECs) to either migrate or form vascular networks on Matrigel.
Result
Our results showed that the conditioned medium from ADC-TAFs and SCC-TAFs induced an increase in human endothelial cell migration. In contrast, the conditioned medium from ADC-TAFs promoted an increase in angiogenesis that was selectively inhibited by nintedanib, whereas such inhibition was not observed in SCC-TAFs.
Conclusion
Our results reveal that nintedanib inhibits the pro-angiogenic effects elicited by factors secreted by ADC-TAFs but not SCC-TAFs, thereby supporting that angiogenesis may be regulated by TAFs through distinct mechanisms in ADC and SCC.
