Dottoressa di ricerca

ciclo: XXXV

Titolo della tesi: EMT/autophagy crosstalk: role of the aberrant expression of the mesenchymal FGFR2c isoform in epithelial tumorigenesis

In epithelial context the aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells induces impaired differentiation inhibition of autophagy as well as the induction of the epithelial-mesenchymal transition (EMT). Considering the widely proposed negative loop linking autophagy and EMT in the early steps of carcinogenesis, in this thesis work we investigated the possible involvement of FGFR2c aberrant expression and signalling in orchestrating this crosstalk. In human keratinocytes context, biochemical, molecular, quantitative immunofluorescence analysis and in vitro invasion assays, coupled to the use of specific substrate inhibitors and transient or stable silencing approaches, showed that AKT/MTOR and PKCε are the two hub signalling pathways, downstream FGFR2c, intersecting with each other in the control of both the inhibition of autophagy and the induction of EMT and invasive behavior. These results indicate that the out of context expression of FGFR2c, could represent a key upstream event responsible for the establishment of a negative interplay between autophagy and EMT. FGFR2 isoform switch is recognized as one of the oncogenic events occurring during pancreatic carcinogenesis, whose contribution in EMT induction and cell invasion, as well as in the dysregulation of autophagy still appears controversial. In fact, 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 PKC 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 PKC 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.

Produzione scientifica

11573/1677970 - 2023 - FGFR2c Upregulation Contributes to Cancer-Associated Fibroblast Program Activation and to Enhanced Autophagy in Actinic Keratosis-Derived Dermal Fibroblasts. A Possible Role in Precancerous Cell/Stromal Cell Crosstalk
Guttieri, Luisa; Raffa, Salvatore; Salerno, Gerardo; Bigi, Rachele; Persechino, Flavia; Visco, Vincenzo; Torrisi, Maria Rosaria; Ranieri, Danilo; Belleudi, Francesca - 01a Articolo in rivista
rivista: BIOLOGY (Basel : MDPI) pp. 1-20 - issn: 2079-7737 - wos: WOS:000957177800001 (1) - scopus: 2-s2.0-85152406980 (3)

11573/1614981 - 2022 - Zinc Supplementation Enhances the Pro-Death Function of UPR in Lymphoma Cells Exposed to Radiation
Gonnella, Roberta; Guttieri, Luisa; Gilardini Montani, Maria Saveria; Santarelli, Roberta; Bassetti, Erica; D'orazi, Gabriella; Cirone, Mara - 01a Articolo in rivista
rivista: BIOLOGY (Basel : MDPI) pp. 1-11 - issn: 2079-7737 - wos: WOS:000758514000001 (7) - scopus: 2-s2.0-85123249134 (7)

11573/1657122 - 2022 - The FGFR2c/PKCε axis controls MCL-1-Mediated invasion in pancreatic ductal adenocarcinoma cells: perspectives for innovative target therapies
Ranieri, Danilo; French, Deborah; Persechino, Flavia; Guttieri, Luisa; Torrisi, Maria Rosaria; Belleudi, Francesca - 01a Articolo in rivista
rivista: BIOMEDICINES (Basel : MDPI) pp. 1-14 - issn: 2227-9059 - wos: WOS:000831972900001 (0) - scopus: 2-s2.0-85137306141 (0)

11573/1542801 - 2021 - Ire1 alpha/xbp1 axis sustains primary effusion lymphoma cell survival by promoting cytokine release and stat3 activation
Gonnella, R.; Gilardini Montani, M. S.; Guttieri, L.; Romeo, M. A.; Santarelli, R.; Cirone, M. - 01a Articolo in rivista
rivista: BIOMEDICINES (Basel : MDPI) pp. 1-11 - issn: 2227-9059 - wos: WOS:000622162300001 (18) - scopus: 2-s2.0-85100188279 (17)

11573/1553792 - 2021 - Expression profile of fibroblast growth factor receptors, keratinocyte differentiation markers, and epithelial mesenchymal transition-related genes in actinic keratosis. A possible predictive factor for malignant progression?
Persechino, F.; Ranieri, D.; Guttieri, L.; Nanni, M.; Torrisi, M. R.; Belleudi, F. - 01a Articolo in rivista
rivista: BIOLOGY (Basel : MDPI) pp. 1-16 - issn: 2079-7737 - wos: WOS:000642738700001 (5) - scopus: 2-s2.0-85104967295 (6)

11573/1563001 - 2021 - Expression of the e5 oncoprotein of hpv16 impacts on the molecular profiles of emt-related and differentiation genes in ectocervical low-grade lesions
Ranieri, D.; French, D.; Raffa, S.; Guttieri, L.; Torrisi, M. R.; Belleudi, F. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. 6534- - issn: 1661-6596 - wos: WOS:000666306500001 (6) - scopus: 2-s2.0-85108067131 (6)

11573/1581250 - 2021 - Role of fgfr2c and its pkcε downstream signaling in the control of emt and autophagy in pancreatic ductal adenocarcinoma cells
Ranieri, D.; Guttieri, L.; Raffa, S.; Torrisi, M. R.; Belleudi, F. - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. - - issn: 2072-6694 - wos: WOS:000708259000001 (3) - scopus: 2-s2.0-85116233439 (3)

11573/1509797 - 2021 - The aberrant expression in epithelial cells of the mesenchymal isoform of FGFR2 controls the negative crosstalk between EMT and autophagy
Ranieri, D.; Nanni, M.; Guttieri, L.; Torrisi, M. R.; Belleudi, F. - 01a Articolo in rivista
rivista: JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (Bucharest : Foundation for Cellular and Molecular Medicine.) pp. - - issn: 1582-1838 - wos: WOS:000619806800001 (5) - scopus: 2-s2.0-85101136353 (4)

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