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J. Alcaraz
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.09 - Premature Fibroblast Senescence in Large Cell Carcinoma Provides Enhanced Growth and Invasive Advantages to Cancer Cells in Culture and in vivo (ID 5352)
15:20 - 15:26 | Author(s): J. Alcaraz
- Abstract
- Presentation
Background:
Tumor-associated fibroblasts (TAFs) are increasingly regarded as essential co-conspirators for tumor progression in all solid tumors including non-small cell lung cancer. While most TAFs exhibit activation markers indicative of a myofibroblast-like phenotype, senescence markers have been reported in a growing list of selected cancer types only. However, the presence of senescent TAFs in lung cancer remains undefined. Assessing senescence in lung TAFs is important because previous studies have reported that senescent TAFs enhances tumor growth, which is in marked contrast with the widely accepted tumor-suppressive role of senescence in cancer cells.
Methods:
We examined common senescence markers in patient derived lung TAFs from the 3 major non-small cell lung cancer (NSCLC) subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Given the difficulties in gathering LCC-TAFs owing to the lower prevalence of LCC compared to the other subtypes, primary fibroblasts from 2 independent fibroblast collections were used. Senescence markers included senescence-associated beta-galactosidase, permanent growth arrest and spreading.
Results:
We found an enrichment of the myofibroblast-like phenotype in TAFs regardless their histologic subtype, yet senescence was observed in LCC-TAFs only regardless their neuroendocrine status. Likewise, co-culturing normal lung fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to induce senescence, and this induction was prevented in the presence of an antioxidant, indicating that it is mediated through oxidative stress. Remarkably, senescent fibroblasts provided growth and invasive advantages to LCC cells in culture and in vivo beyond those effects provided by control (non-senescent) fibroblasts.
Conclusion:
Our findings expand recent evidence that challenges the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless their histologic subtype. Of note, because LCC often distinguishes itself in the clinic by its aggressive nature, our findings support that senescent or senescent-like TAFs may contribute to the selective aggressive behavior of LCC tumors.
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OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:L.M. Montuenga, J. Heymach
- Coordinates: 12/06/2016, 11:00 - 12:30, Stolz 2
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OA11.06 - Role of Fibroblasts in the Subtype-Specific Therapeutic Effects of Nintedanib in Non-Small Cell Lung Cancer (NSCLC) (ID 5029)
12:20 - 12:30 | Author(s): J. Alcaraz
- Abstract
- Presentation
Background:
There is growing evidence that tumor-associated fibroblasts (TAFs) play a major role in critical steps of tumor progression in solid tumors including NSCLC. However the role of TAFs in regulating the response to targeted therapies is poorly understood. One of such targeted therapies is nintedanib (NTD), a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients. Although the therapeutic effects of NTD in lung cancer have been associated with its anti-angiogenic functions, NTD has also been shown to exhibit anti-fibrotic effects in patients with idiopathic pulmonary fibrosis. Since lung fibrosis is largely driven by activated fibroblasts/myofibroblasts, and TAFs are positive for myofibroblasts markers, it is conceivable that NTD anti-tumor effects may be additionally driven through its direct action on lung TAFs. The main goal of this study was to analyze the latter hypothesis.
Methods:
Patient derived lung TAFs from ADC and SCC patients as well as paired control fibroblasts from non-malignant pulmonary tissue were exposed to increasing concentrations of NTD and analyzed for growth and activation upon stimulation with growth factors and TGF- β1, respectively. Activation markers included alpha-smooth muscle actin and collagen-I.
Results:
We found that NTD exhibited a dual inhibitory role in TAFs in terms of growth and TGF-β1-induced activation in a subtype-specific fashion. Specifically, NTD-mediated growth inhibition was larger in SCC-TAFs than in ADC-TAFs, which correlated with the larger Erk signaling previously reported by our group in SCC-TAFs in the absence of mitogenic stimuli. Conversely, inhibition by NTD of TGF-β1-mediated activation was larger in ADC-TAFs than SCC-TAFs. Likewise, NTD inhibited the growth and invasive advantages of ADC cancer cells in vitro elicited by the conditioned medium of ADC-TAFs treated with TGF-β1 compared to those advantages elicited in the absence of NTD. These results reveal for the first time that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD.
Conclusion:
TAFs in vivo are largely activated and quiescent, and TGF-β1 is a potent fibroblast activator that is frequently upregulated in lung cancer and associated with poor prognosis. Based on these previous observations, we argue that our new findings strongly suggest that the selective therapeutic advantage observed for NTD in ADC patients may be in part related to its selective inhibition of TGF-β1-dependent activation of ADC-TAFs. These findings provide novel mechanistic insights on the subtype-specific therapeutic effects of NTD in NSCLC.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-076 - DNA Methylation Profiling Unravels a TGF-β Hyperresponse in Tumor Associated Fibroblasts from Lung Cancer Patients (ID 5356)
14:30 - 14:30 | Author(s): J. Alcaraz
- Abstract
Background:
Tumor associated fibroblasts (TAFs) are drawing increasing attention as potential therapeutic targets owing to its direct implication in major steps of tumor progression in solid tumors including non-small cell lung cancer. Accordingly, there is growing interest in defining the aberrant molecular differences between normal and TAFs that support tumor progression. For this purpose, we recently conducted a genome-wide DNA methylation profiling of TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer patients, and reported a widespread hypomethylation concomitantly with a focal gain of DNA methylation indicative of a marked epigenetic reprogramming. Of note, the aberrant epigenome of lung TAFs had a global impact in gene expression and a selective impact on the TGF-β pathway, including the hypermethylation of SMAD3, which is an important transcription factor of the TGF-β pathway. However, the functional implications of the aberrant TGF-β pathway in lung TAFs remains undefined.
Methods:
Patient-derived TAFs and paired control fibroblasts from either adenocarcinoma (ADC) or squamous cell carcinoma (SCC) patients were stimulated with TGF-β1 and their responses were examined in terms of activation and contractility. Activation markers included expression of alpha-smooth muscle actin (α-SMA) and collagen-I, which were assessed by western-blotting and qRT-PCR, respectively. The contractility of single fibroblasts was assessed by traction force microscopy.
Results:
We found a larger expression of activation markers including α-SMA and collagen-I in TAFs compared to control fibroblasts. Likewise, TGF-β1 elicited a larger contractility in TAFs than in control fibroblasts as assessed by traction force microscopy. Of note, these results were consistent with previous observations reported on skin fibroblasts from Smad3 knock-out mice.
Conclusion:
Our findings reveal that lung TAFs are hyperresponsive to TGF-β1, even though their expression of SMAD3 is epigenetically down-regulated. This aberrant response to TGF-β1 may underlie the expansion and/or maintenance of the tumor-promoting desmoplastic stroma in lung cancer.
