Abstract 3366: The mechanical microenvironment and β1/FAK signaling control fibroblast accumulation in lung cancer

Abstract

Abstract There is growing interest in targeting the abnormal accumulation of fibroblasts in solid tumors. 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 in cultured TAFs from two major subtupes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQC). We reported that the increased population of SQC-TAFs is largely driven by matrix stiffening rather than by soluble growth factors. In contrast, ADC-TAFs were poorly responsive to exogenous mechanical cues. We also reported that the differential mechanoresponses in SQC- and ADC-TAFs were associated with both larger mechanosensing through FAK and β1 integrin expression in the former TAFs. To get more insights into the latter mechanoregulatory circuit, we forced either β1 integrin activation or FAK expression in fibroblasts cultured in soft (normal-like) gels. Both conditions were sufficient to increase fibroblast population to values comparable to those found in stiff (tumor-like) gels. These data reveal that an abnormally high intrinsic mechanosensing through β1 integrins and FAK can bypass the inhibitory (protective) role of an extrinsic soft microenvironment. Moreover, these results suggest that inhibiting either β1 integrin or FAK signaling may be a suitable approach to target tumor-supporting TAFs in SQC. Citation Format: Jordi Alcaraz, Marta Gabasa, Óscar Busnadiego, Fernando Rodríguez-Pascual, Pere Gascón, Noemí Reguart. The mechanical microenvironment and β1/FAK signaling control fibroblast accumulation in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3366. doi:10.1158/1538-7445.AM2015-3366