The FGFRs are RTKs expressed by tissue-specific alternative splicing in epithelial IIIb or mesenchymal IIIc isoforms. In the epithelial-context, while FGFR2b acts as tumor suppressor, FGFR2c appears to play an oncogenic role. Based on our recent observation that the FGFR2b/FGFR2c switching and the ectopic expression of FGFR2c induce EMT and tumorigenic features in human keratinocytes, in this project we plan to investigate the possible involvement of PKCepsilon and PKCalpha downstream pathways in these FGFR2c-induced pathological outcomes. Our research project would significantly help to clarify the network of oncogenic pathways activated downstream FGFR2c in epithelial context, contributing to the advancement of knowledge of the complex molecular events underlying RTK signaling deregulation during carcinogenesis.
Since the deregulation of FGFR downstream signaling can play pivotal oncogenic roles, several reports and our recent findings have definitely assessed the crucial contribution of the out-of-context paracrine FGF signaling consequent to the FGFR isoform switching, which leads to the expression of mesenchymal FGFRc isoforms in epithelial cells.
On the base of these evidences, the role of FGFRs in tumorigenesis has been well-established and very promising therapeutic strategy has been recently focused on FGFR targeting, through the use of non-selective or selective tyrosine kinase inhibitors, monoclonal antibodies and ligand traps.
Even if the clinical response of each anti-FGFR cancer therapy must be carefully evaluated and compared with other possible oncogenic drivers in each individual cancer type (taken into account the resistance events, which could be tried to be bypassed with the combination with other agents), our research project could significantly contribute to dissect the multiple molecular elements of the complex oncogenic signaling network activated downstream FGFR2c, contributing to the advancement of knowledge of the complex molecular events leading to cancerogenesis.