The epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) are activated by gene amplification, mutation and overexpression in bladder cancer, which drives tumor development and progression. Both EGFR and FGFR inhibitors are currently being tested in clinical trials. However, bladder cancer (BC) cells show remarkably heterogeneous sensitivities to both inhibitors, and the molecular determinants of this heterogeneity are presently unclear. Therefore, in this study, using selective EGFR and FGFR inhibitors in BC cells, we demonstrated that FGFR3 and FGFR1 play largely non-overlapping roles in mediating proliferation and invasion in the distinct “epithelial” and “mesenchymal” subsets of human BC cells. Furthermore, we examined the sensitivities to FGFR3 and EGFR inhibition in a panel of human BC cells, and found that FGFR3 and EGFR dependency are mutually exclusive biological phenotypes controlled by PPARγ-FABP4 pathway. This study significantly extends and complements our knowledge of molecular mechanism that mediates growth receptor dependent proliferation in BC
