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M. Puig
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-061 - Tumor-Associated Fibroblasts Increased Density in Non-Small Cell Lung Cancer Is Mediated by Microenvironment Through β1/FAK Signaling (ID 2250)
09:30 - 09:30 | Author(s): M. Puig
- Abstract
Background:
The current paradigm assumes that the abundance of tumor-associated fibroblasts (TAFs) is largely driven by soluble growth factors as in generic repair responses irrespective of the tumor type or subtype. We recently challenged this assumption by showing that the increased population of lung cancer squamous (SQC)-TAFs in culture was largely driven by matrix stiffening rather than by soluble growth factors (i.e. serum), whereas lung adenocarcinoma (ADC)-TAFs were poorly responsive to exogenous mechanical cues (i.e. matrix rigidity). Moreover, we described that the differential mechano-responses observed in SQC- and ADC-TAFs were associated with increased FAK and a β1 integrin expression.
Methods:
To check whether β1 integrin was necessary for the larger TAF density observed, we treated CCD-19Lu fibroblasts with increasing concentrations of the β1 integrin-inhibitory monoclonal antibody AIIB2 and the monoclonal b1 integrin–activating antibody TS2/16. To further confirm the requirement of β1 integrin through FAK we either depleted or overexpressed FAK in mouse embryonic fibroblasts (MEFs) by transducing with adenoviral infection with FAK (Adv-FAK).
Results:
We observed a dose-dependent decrease in cell density in cells cultured in stiff (30 kPa) gels treated with AIIB2. Moreover, activating β1 integrin with TS2/16 antibody was sufficient to increase both cell density and FAKpY397 expression of CCD-19Lu fibroblasts in soft (1 kPa) gels. As in CCD-19 Lu fibroblasts, matrix stiffening enhanced cell density and FAK expression in wild-type MEFs (FAK[+/+]), whereas such increases were not observed in FAK null fibroblasts (FAK[-/-]). Conversely, overexpressing FAK in wild-type MEFs (FAK[+/+]) was sufficient to markedly increase both cell density and FAK expression in 1 kPa gels compared with control MEFs.
Conclusion:
Abnormally high intrinsic mechano-sensing through β1 integrins and FAK can bypass the inhibitory (protective) role of an extrinsic soft microenvironment. Inhibition of either β1 integrin or FAK signaling may be a suitable approach to target tumor-supporting TAFs in SQC-NSCLC.
