Role of FGFR2c and Its PKCε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells

SIMPLE SUMMARY: This work aims to assess the contribution of the aberrant expression of the mesenchymal FGFR2c and the triggering of the downstream PKCε signaling in selected cell lines from pancreatic ductal adenocarcinoma (PDAC), a malignancy characterized by acquired EMT signature and deregulated autophagy. The results show that: (i) FGFR2c expression appears to impact on cell responsiveness to FGF2 in terms of intracellular signaling activation and upregulation of EMT expression profile and (ii) PKCε signaling, activated in PANC-1 cell line, expressing high levels of FGFR2c, is involved in both receptor-mediated enhancement of EMT and inhibition of autophagy. Overall, this study suggests that PKCε could be a possible therapeutic target whose inactivation could contribute in counteracting tumor aggressive phenotype. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant malignancy characterized by a high malignant phenotype including acquired EMT signature and deregulated autophagy. Since we have previously described that the aberrant expression of the mesenchymal FGFR2c and the triggering of the downstream PKCε signaling are involved in epidermal carcinogenesis, the aim of this work has been to assess the contribution of these oncogenic events also in the pancreatic context. Biochemical, molecular and immunofluorescence approaches showed that FGFR2c expression impacts on PDAC cell responsiveness to FGF2 in terms of intracellular signaling activation, upregulation of EMT-related transcription factors and modulation of epithelial and mesenchymal markers compatible with the pathological EMT. Moreover, shut-off via specific protein depletion of PKCε signaling, activated by high expression of FGFR2c resulted in a reversion of EMT profile, as well as in a recovery of the autophagic process. The detailed biochemical analysis of the intracellular signaling indicated that PKCε, bypassing AKT and directly converging on ERK1/2, could be a signaling molecule downstream FGFR2c whose inhibition could be considered as possible effective therapeutic approach in counteracting aggressive phenotype in cancer.