Fibroblast growth factors (FGFs) and their receptors (FGFRs) comprise a potent intracellular signaling system promoting cell growth, survival and epithelial-mesenchymal transition (EMT) in tumors including malignant pleural mesothelioma (MPM). EMT is implicated in cancer progression, but its role in MPM is unclear. MPM occurs in three main histological subtypes – epithelioid, sarcomatoid and biphasic – with sarcomatoid being most aggressive and having a morphological resemblance to cells undergoing EMT. While these subtypes are characterized by morphological growth pattern, aggressiveness and patient prognosis, the biological mechanisms responsible are poorly understood.
FGF2 treatment induced morphological changes reminiscent of EMT and aggressive behavior such as scattering, increased migration, proliferation and invasiveness. To further investigate the role of FGF signaling, we engineered Opto-FGFR1. In this modified FGFR1 the ligand-binding domain is replaced by a light-activated domain. Opto-FGFR1 is therefore insensitive to endogenous ligands, but instead can be activated by blue light enabling contactless spatially and temporally precise activation.
Stimulation of the transgenic cells with light increased cell growth and led to a change from epithelioid to sarcomatoid morphology, similar to the effects of FGF2 treatment. Pharmacological FGFR inhibition could prevent these changes and, in cell lines with sarcomatoid-like shape, reversed scattering and induced a more epithelioid morphology.
Gene expression analysis showed an overlap with established EMT markers, but also identified several novel potential markers of these phenotypic changes. In unsupervised clustering, the gene expression profiles of control- or cytokine-treated cells were associated with those of epithelioid and sarcomatoid MPM, respectively.
Our data characterise FGFR-mediated signals as important players in MPM aggressiveness and the morphological and behavioral plasticity of mesothelioma cells, leading to a better understanding of the link between the MPM histological subtypes and their influence on patient outcome. Also, light-activated Opto-FGFR1 was able to mimic complex morphogenic and mitogenic cell behaviour induced by FGF2 with temporal and spatial precision providing a powerful new tool to study and manipulate cellular signals and behaviour.