Ricerc@Sapienza

Fibroblast growth factor receptors (FGFRs) regulate the epithelial-stromal homeostasis; however, when deregulated and expressed out of context, also by tissue-specific isoform switching, they can play oncogenic roles. We have previously demonstrated that FGFR2b is involved in keratinocytes differentiation (Rosato et al., 2018), while 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., 2016, Ranieri et al., 2018). Therefore, the possibility that FGFR2 isoform switching in the epithelial context could establish alternative physiological versus oncogenic signaling networks, most of the molecular players of which are still unknown, encouraged us to further identify possible divergences between FGFR2 isoforms in term of activation dynamics of common and newly identified isoform-specific signaling pathways, that could explain their opposite biological outcomes. Moreover, on the light of the widely proposed possibility that RTK signaling and endocytosis could affect each other, we also plan to investigate if and to what extent the endocytic fate of FGFR2c could contribute to the establishment of its signaling and of its tumorigenic outcome in epithelial context. To this aim we propose: i) to investigate if FGFR2 isoform switch could dysregulate the receptor endocytic process in epithelial cells and ii) to establish the contribution of this possible deregulation in receptor intracellular trafficking and signaling, as well as in the receptor-mediated induction of EMT and invasive phenotype.
The expected results may contribute to clarify the molecular interplay linking FGFR signaling, endocytosis and pathological EMT, which could be triggered by FGFR2 isoform switch and consequent aberrant expression of the oncogenic FGFR2c splicing receptor variant in the epithelial context, leading to carcinogenesis.