Ricerc@Sapienza

Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant malignancy driven by the "undruggable", constitutively active KRAS, which made the search for new therapeutic strategies bypassing this oncogenic substrate very urgent. Since the FGFR2 altered splicing and the triggering of PKCepsilon downstream signaling have been recently described by us as involved in the early steps of epidermal carcinogenesis, aim of this research project will be to assess if and to what extent these events could contribute to the induction of EMT, to the deregulation of autophagy and possibly to the control of their interplay in the context of pancreatic cancer cells. Biochemical, molecular and immunofluorescence approaches will be applied in different PDAC cell lines, selected for different expression of mesenchymal FGFR2c isoform and poor levels of its epithelial counterpart FGFR2b, in order to check the possible correlation between FGFR2c expression and the induction of EMT-related transcription factors in response to FGF2, as well as the modulation of epithelial/mesenchymal markers and changes in cell morphology compatible with the pathological EMT. Specific inhibitors for FGFR2 tyrosine kinase activity, such as SU5402, and receptor depletion via shRNA will be used to confirm the direct dependence of the events possibly observed on FGFR2c expression and signaling. Parallel experiments of gene silencing by shRNA will be also performed to assess the contribution of PKCepsilon and to dissect the signaling network downstream this PKC isoform possibly responsible for FGFR2c-dependent modulation of EMT and autophagy.
Overall, our research project aims to contribute to the identification of new molecular players at the crossroad between FGF/FGFR aberrant signaling, EMT and dysregulated autophagy that would represent new key biomarkers and targets for innovative therapeutic strategies aimed to counteract tumor development and/or to overcome RAS-dependent "undruggability" in PDAC.