title: Adipocytes WNT5a mediated dedifferentiation: a possible target in pancreatic cancer microenvironment.
abstract: A significant epidemiological association between obesity and pancreatic ductal adenocarcinoma (PDAC) has previously been described, as well as a correlation between the degree of pancreatic steatosis, PDAC risk and prognosis. The underlying mechanisms are still not completely known.After co-culture of 3T3-L1 adipocytes and MiaPaCa2 with an in vitro transwell system we observed the appearance of fibroblast-like cells, along with a decrease in number and size of remaining adipocytes. RT-PCR analyses of 3T3-L1 adipocytes in co-culture showed a decrease in gene expression of typical markers of mature adipocytes, in parallel with an increased expression of fibroblast-specific and reprogramming genes. We found an increased WNT5a gene and protein expression early in MiaPaCa2 cells in co-culture. Additionally, EMSA of c-Jun and AP1 in 3T3-L1 demonstrated an increased activation in adipocytes after co-culture. Treatment with WNT5a neutralizing antibody completely reverted the activation of c-Jun and AP1 observed in co-cultured adipocytes.Increasing doses of recombinant SFRP-5, a competitive inhibitor for WNT5a receptor, added to the co-culture medium, were able to block the dedifferentiation of adipocytes in co-culture.These data support a WNT5a-mediated dedifferentiation process with adipocytes reprogramming toward fibroblast-like cells that might profoundly influence cancer microenvironment.
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Zoico
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Darra
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Vanni
authors.initials: V
authors.lastname: Rizzatti
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Budui
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Franceschetti
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Mazzali
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Rossi
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fantin
authors.affiliation: Department of Life and Reproduction Sciences, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Menegazzi
authors.affiliation: Department of Experimental and Clinical Medicine, Center of Obesity-University of Ancona (Politecnica delle Marche), Ancona, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.affiliation: Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Zamboni
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D054337:Cell Dedifferentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D059016:Tumor Microenvironment; D000071818:Wnt-5a Protein / Q000378:metabolism*
chemical_list: D000071818:Wnt-5a Protein
keywords: WNT5a; adipocytes; cell dedifferentiation; pancreatic cancer; tumor microenvironment