Autophagy is an auto-digestion process crucial to ensure maintenance of cellular homeostasis. On the last years we have demonstrated that the epithelial splicing variant of the fibroblast growth factor receptor 2 (FGFR2b) triggers autophagy in human keratinocytes and that this event is required for receptor-dependent differentiation (Belleudi et al., 2014, Belleudi et al., 2015, Nanni et al., 2018). On the other hand, our recent reports indicated that the aberrant expression of the FGFR2c mesenchymal isoform in the epithelial context induces impaired differentiation, epithelial-mesenchymal transition (EMT) and tumorigenic features (Ranieri et al., 2015, Ranieri et al., 2016, Ranieri et al., 2018). These published results coupled to few preliminary observations encourage us to suppose a potential role of the aberrant expression of the oncogenic FGFR2c splicing variant in the deregulation of the negative crosstalk between autophagy and EMT in epithelial cells. To evaluate the impact of FGFR2 altered splicing on this crosstalk, we plan to assess if the EMT triggered by the FGFR2c aberrant expression and signaling in epithelial context could be the consequence of a deregulated autophagy in a negative crosstalk. To this aim we propose: i) to verify if FGFR2c could impact on autophagy and if the possible dysfunction of the autophagic process could play a role in receptor-mediated induction of EMT and tumorigenic features; ii) to identify the molecular mechanisms at the crossroad between FGFR2c-mediated autophagy and EMT. The expected results may contribute to clarify the molecular interplay linking autophagy and pathological EMT, which could be triggered by the aberrant expression of the oncogenic FGFR2c splicing receptor variant in the epithelial context, leading to carcinogenesis.
It is well established that deregulated FGF/FGFR signaling may play opposite oncogenic or tumor suppressive roles, depending on the cellular contexts. Among the postulated mechanisms of oncogenic FGFR signaling - including gene amplification, activating mutations and gene fusions/translocations - we and others have demonstrated the key contribution of the out-of-context autocrine or paracrine FGF signaling and of the aberrant receptor splicing leading to the expression of mesenchymal FGFRc isoforms in epithelial cells. Consistent with these roles played by FGFR in carcinogenesis, a growing number of preclinical and early clinical data indicate that targeting FGFRs, through the use of non-selective or selective tyrosine kinase inhibitors, monoclonal antibodies and ligand traps, can be a very promising therapeutic strategy, especially if in combination with other agents. However, increasing evidences are also pointing to the variable effects of anti-FGFR cancer therapies, which exert in some clinical settings a low response efficacy and development of drug resistance. In fact, although some FGFR mutations are potential targets for monotherapy, others do not appear to be suitable biomarkers of response and need to be carefully evaluated and compared with other possible oncogenic drivers in each individual cancer type. Also the appearance of resistance to FGFR targeting seems largely due to gatekeeper mutations in FGFR kinase domain, or to the activation of alternative receptor tyrosine kinases, which must be accurately taken into account.
In this scenario, our research project could significantly help to the identification of multiple, molecular hubs at the crossroad between autophagy and EMT, contributing to the advancement of knowledge of the complex molecular events leading to tumorigenesis and enabling to characterize new biomarkers and targets for innovative personalized prognostic and diagnostic tools as well as therapeutic strategies to revert the early steps of cancerogenesis or to overcome the acquired drug resistance. Based on these expected results and their possible clinical applications, the impact of our project would be also envisioned as a further contribution to the solution of social, economic and public health problems related to the most innovative management of neoplastic diseases as requested by the more recent guidelines in precision oncology.