The Mutant p53-Driven Secretome Has Oncogenic Functions in Pancreatic Ductal Adenocarcinoma Cells
Giovanna Butera,
Jessica Brandi,
Chiara Cavallini,
Aldo Scarpa,
Rita T. Lawlor,
Maria Teresa Scupoli,
Emílio Marengo,
Daniela Cecconi,
Marcello Manfredi,
Massimo Donadelli
Affiliations
Giovanna Butera
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
Jessica Brandi
Department of Biotechnology, University of Verona, 37134 Verona, Italy
Chiara Cavallini
Research Center LURM (Interdepartmental Laboratory of Medical Research), University of Verona, 37134 Verona, Italy
Aldo Scarpa
Department of Diagnostics and Public health, Section of Pathology, University of Verona, 37134 Verona, Italy
Rita T. Lawlor
ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, 37134 Verona, Italy
Maria Teresa Scupoli
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
Emílio Marengo
Department of Sciences and Technological Innovation, University of Piemonte Orientale, 28100 Novara, Italy
Daniela Cecconi
Department of Biotechnology, University of Verona, 37134 Verona, Italy
Marcello Manfredi
Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Italy, ISALIT, Spin-off at the University of Piemonte Orientale, 28100 Novara, Italy
Massimo Donadelli
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
The cancer secretome is a rich repository of useful information for both cancer biology and clinical oncology. A better understanding of cancer secretome is particularly relevant for pancreatic ductal adenocarcinoma (PDAC), whose extremely high mortality rate is mainly due to early metastasis, resistance to conventional treatments, lack of recognizable symptoms, and assays for early detection. TP53 gene is a master transcriptional regulator controlling several key cellular pathways and it is mutated in ~75% of PDACs. We report the functional effect of the hot-spot p53 mutant isoforms R175H and R273H on cancer cell secretome, showing their influence on proliferation, chemoresistance, apoptosis, and autophagy, as well as cell migration and epithelial-mesenchymal transition. We compared the secretome of p53-null AsPC-1 PDAC cells after ectopic over-expression of R175H-mutp53 or R273H-mutp53 to identify the differentially secreted proteins by mutant p53. By using high-resolution SWATH-MS technology, we found a great number of differentially secreted proteins by the two p53 mutants, 15 of which are common to both mutants. Most of these secreted proteins are reported to promote cancer progression and epithelial-mesenchymal transition and might constitute a biomarker secreted signature that is driven by the hot-spot p53 mutants in PDAC.
