Of FGFR2c, is involved in both receptor-mediated enhancement of EMT and inhibition of autophagy. Overall, this study suggests that PKC could possibly be a possible therapeutic target whose inactivation could contribute in counteracting tumor aggressive phenotype. Abstract: Pancreatic ductal adenocarcinoma (PDAC) is often a treatment-resistant malignancy characterized by a high malignant phenotype such as acquired EMT signature and RHPS4 Biological Activity deregulated autophagy. Since we’ve previously described that the aberrant expression from the mesenchymal Curdlan Biological Activity FGFR2c and the triggering in the downstream PKC signaling are involved in epidermal carcinogenesis, the aim of this perform 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 with regards to intracellular signaling activation, upregulation of EMT-related transcription components and modulation of epithelial and mesenchymal markers compatible with the pathological EMT. In addition, shut-off by means of specific protein depletion of PKC signaling, activated by higher expression of FGFR2c resulted in a reversion of EMT profile, at the same time as within a recovery in the autophagic procedure. The detailed biochemical analysis of the intracellular signaling indicated that PKC, bypassing AKT and directly converging on ERK1/2, might be a signaling molecule downstream FGFR2c whose inhibition may very well be regarded as as you can productive 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 an open access report distributed beneath the terms and situations of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ four.0/).1. Introduction The pancreatic ductal adenocarcinoma (PDAC) is amongst the most lethal malignancies characterized by high frequency of activating mutations in KRAS gene [1,2]. Within this context, PI3K-AKT-MTOR and Raf-MEK-ERK signaling have been described because the key RAS downstream pathways, strongly intersecting with every other, involved within the manage of numerous oncogenic outcomes, which includes cell growth dysregulation, epithelial to mesenchymal transition (EMT) induction and autophagic enhancement [2]. Since KRASCancers 2021, 13, 4993. https://doi.org/10.3390/cancershttps://www.mdpi.com/journal/cancersCancers 2021, 13,2 ofis thought of an “undruggable” signaling molecule, more and more relevance has been offered towards the identification of new signaling molecules, possibly bypassing RAS, whose inactivation could substantially influence around the PDAC aggressive phenotype. PKC-mediated signaling has been described as one of the most important RAS-independent pathways activated by various receptor tyrosine kinases (RTKs), such as fibroblast growth issue receptors (FGFRs) [6], whose dysregulation considerably contributes to cancer development [7]. Regarding this subject, we have lately demonstrated a central contribution for the PKC isoform in the oncogenic outcomes established by the signaling of the mesenchymal isoform of FGFR2 (FGFR2c) when expressed within the epithelial context [8,9]. Even though the aberrant expressions of FGFR2c or FGFR2 altered splicing have already been previousl.