title: The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease in need of prognostic markers to address therapeutic choices. We have previously shown that alternative splicing of the actin regulator, hMENA, generates hMENA11a, and hMENAΔv6 isoforms with opposite roles in cell invasion. We examined the expression pattern of hMENA isoforms by immunohistochemistry, using anti-pan hMENA and specific anti-hMENA11aantibodies, in 285 PDACs, 15 PanINs, 10 pancreatitis, and normal pancreas. Pan hMENA immunostaining, absent in normal pancreas and low-grade PanINs, was weak in PanIN-3 and had higher levels in virtually all PDACs with 64% of cases showing strong staining. Conversely, the anti-invasive hMENA11aisoform only showed strong staining in 26% of PDAC. The absence of hMENA11ain a subset (34%) of pan-hMENA-positive tumors significantly correlated with poor outcome. The functional effects of hMENA isoforms were analyzed by loss and gain of function experiments in TGF-β1-treated PDAC cell lines. hMENA11aknock-down in PDAC cell lines affected cell-cell adhesion but not invasion. TGF-β1 cooperated with β-catenin signaling to upregulate hMENA and hMENAΔv6 expression but not hMENA11aIn the absence of hMENA11a, the hMENA/hMENAΔv6 up-regulation is crucial for SMAD2-mediated TGF-β1 signaling and TGF-β1-induced EMT. Since the hMENA isoform expression pattern correlates with patient outcome, the data suggest that hMENA splicing and related pathways are novel key players in pancreatic tumor microenvironment and may represent promising targets for the development of new prognostic and therapeutic tools in PDAC.
authors.affiliation: Tumour Immunology and Immunotherapy Unit, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Melchionna
authors.affiliation: Tumour Immunology and Immunotherapy Unit, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Iapicca
authors.affiliation: Tumour Immunology and Immunotherapy Unit, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Modugno
authors.affiliation: Tumour Immunology and Immunotherapy Unit, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Trono
authors.affiliation: Biostatistics and Scientific Direction, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: ARC-NET Research Center, Department of Pathology and Diagnostics, University of Verona , Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: ARC-NET Research Center, Department of Pathology and Diagnostics, University of Verona , Verona, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Cataldo
authors.affiliation: ARC-NET Research Center, Department of Pathology and Diagnostics, University of Verona , Verona, Italy.
authors.forename: Borislav C
authors.initials: BC
authors.lastname: Rusev
authors.affiliation: ARC-NET Research Center, Department of Pathology and Diagnostics, University of Verona , Verona, Italy.
authors.forename: Rita T
authors.initials: RT
authors.lastname: Lawlor
authors.affiliation: Pathology Unit, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Diodoro
authors.affiliation: Medical Oncology, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.affiliation: Hepato-pancreato-biliary Surgery Unit, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Grazi
authors.affiliation: Lawrence Berkeley National Laboratory, University of California , CA, USA.
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.affiliation: ARC-NET Research Center, Department of Pathology and Diagnostics, University of Verona , Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Tumour Immunology and Immunotherapy Unit, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Nisticò
keywords: Actin Cytoskeleton; EMT; PDAC; TGF-β1; hMENA alternative splicing