Autophagy is a degradative pathway playing a pivotal role in ensuring cellular homeostasis and stress response. On the last years we have demonstrated that the epithelial splice variant of fibroblast growth factor receptor 2 (FGFR2b) triggers both differentiation and autophagy, while the aberrant expression of the mesenchymal FGFR2c isoform in epithelial context induces impaired differentiation, EMT and tumorigenic features. More recently we found that FGFR2c also inhibit autophagy in human keratinocytes, impacting on the step of the autophagosome formation. In addition, silencing experiments of depletion of ESRP1, responsible for FGFR2 splicing and consequent FGFR2b expression, indicated that the altered splicing and the isoform switching from FGFR2b to FGFR2c underlie the inhibition of autophagy.
On the light of these recent evidences, in this project we plan: i) to identify the signaling pathways downstream FGFR2c responsible for the receptor-mediated inhibition of the autophagic process; ii) to establish if and how the repression of the autophagic process induced by FGFR2c play a role in receptor-mediated induction of EMT and tumorigenic features; iii) to look for possible key molecular hubs placed at the crossroad between autophagy and EMT. Our possible findings would significantly help to the identification of multiple molecular events regulating both the autophagic process and pathological EMT, contributing to the advancement of knowledge of the complex mechanisms leading to tumorigenesis.
This research project clearly represent the further advancement of our recent studies (proposed in Belleudi, ATENEO 2018), that have clarified the central role of FGFR2c, aberrantly expressed in epithelial context, in the induction of not only impaired differentiation, EMT and tumorigenic features (Ranieri et al., 2016; Ranieri et al., 2018), but also in the deregulation of autophagy (Nanni et al., submitted). Even if FGFR2c-mediated EMT and autophagy are under control by a complex network of signaling pathways only partially overlapping, the two processes probably share hub molecules whose identification will allow to modulate their negative interplay, shifting the balance towards a process or the other. Since we are recently working in dissecting and identifying FGFR2c oncogenic signaling driving EMT and tumorigenic features, in this proposal we plan to advance in knowledge of the negative crosstalk governing EMT and autophagy in cancer, identifying the signaling pathways underlying FGFR2c-mediated inhibition of autophagy and focusing our attention to the few molecular player that could be at the crossroad between the two processes.
Even if 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 in cancer, especially if in combination with other agents, 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, in particular, 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. Therefore, thanks to their possible clinical applications, our studies could have a relevant impact for 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.