Of FGFR2c, is involved in each receptor-mediated enhancement of EMT and inhibition of autophagy. General, this study suggests that PKC may be a possible therapeutic target whose inactivation could contribute in counteracting tumor aggressive phenotype. Abstract: Pancreatic ductal adenocarcinoma (PDAC) is usually a treatment-resistant malignancy characterized by a higher malignant phenotype which includes acquired EMT signature and deregulated autophagy. Since we have previously described that the aberrant expression in the mesenchymal FGFR2c plus the Avadomide Protocol triggering in the downstream PKC signaling are involved in epidermal carcinogenesis, the aim of this function has been to assess the contribution of these oncogenic events also within the pancreatic context. Biochemical, molecular and immunofluorescence approaches showed that FGFR2c expression impacts on PDAC cell responsiveness to FGF2 when it comes to intracellular signaling activation, upregulation of EMT-related transcription things and modulation of epithelial and mesenchymal markers compatible using the pathological EMT. Furthermore, shut-off through distinct protein depletion of PKC signaling, activated by higher expression of FGFR2c resulted in a reversion of EMT profile, too as within a recovery from the autophagic approach. The detailed biochemical evaluation in the intracellular signaling indicated that PKC, bypassing AKT and straight converging on ERK1/2, could be a signaling molecule downstream FGFR2c whose inhibition could be considered as possible helpful therapeutic strategy in counteracting aggressive phenotype in cancer. Keyword phrases: FGFR2c; PDAC; epithelial esenchymal transition (EMT); autophagy; PKCPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Copyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is definitely an open access report distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).1. Introduction The pancreatic ductal adenocarcinoma (PDAC) is amongst the most lethal malignancies characterized by higher frequency of activating mutations in KRAS gene [1,2]. In this context, PI3K-AKT-MTOR and Raf-MEK-ERK signaling have already been described as the principal RAS downstream pathways, strongly intersecting with every single other, involved in the control of many oncogenic outcomes, like cell growth dysregulation, epithelial to mesenchymal transition (EMT) induction and autophagic enhancement [2]. Considering the fact that KRASCancers 2021, 13, 4993. https://doi.org/10.3390/cancershttps://www.mdpi.com/journal/cancersCancers 2021, 13,two ofis regarded as an “undruggable” signaling molecule, far more and much more relevance has been given for the identification of new signaling molecules, possibly bypassing RAS, whose inactivation could significantly effect around the PDAC aggressive phenotype. PKC-mediated signaling has been described as one of many most important RAS-independent pathways activated by several receptor tyrosine kinases (RTKs), including fibroblast growth aspect receptors (FGFRs) [6], whose dysregulation drastically contributes to cancer development [7]. Regarding this subject, we’ve lately demonstrated a central contribution for the PKC isoform D-Glutamic acid supplier inside the oncogenic outcomes established by the signaling from the mesenchymal isoform of FGFR2 (FGFR2c) when expressed inside the epithelial context [8,9]. Even when the aberrant expressions of FGFR2c or FGFR2 altered splicing happen to be previousl.