title: Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells.
abstract: Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5aLowmesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma.Cancer Res; 77(4); 996-1007. ©2016 AACR.
authors.affiliation: IRCSS Casa Sollievo della Sofferenza, ISBReMIT- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Italy. vescovia@gmail.com e.binda@css-mendel.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Binda
authors.affiliation: StemGen SpA, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Visioli
authors.affiliation: Dept. of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giani
authors.affiliation: IRCSS Casa Sollievo della Sofferenza, c/o Instituto Mendel, Rome, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Trivieri
authors.affiliation: Medical Genetics Unit, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Palumbo
authors.affiliation: StemGen SpA, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Restelli
authors.affiliation: IRCSS Casa Sollievo della Sofferenza, ISBReMIT- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Dezi
authors.affiliation: IRCSS Casa Sollievo della Sofferenza, c/o Instituto Mendel, Rome, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: IRCSS Casa Sollievo della Sofferenza, c/o Instituto Mendel, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fusilli
authors.affiliation: National Neurological Institute "C. Besta," Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Legnani
authors.affiliation: Medical Genetics Unit, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.affiliation: National Neurological Institute "C. Besta," Milan, Italy.|Department of Neurosurgery, John Hopkins University, Baltimore, Maryland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Meco
authors.affiliation: Stem Cell Research Unit, Sorrento Therapeutics Inc., San Diego, California.
authors.forename: Rohit
authors.initials: R
authors.lastname: Duggal
authors.affiliation: IRCSS Casa Sollievo della Sofferenza, ISBReMIT- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Italy. vescovia@gmail.com e.binda@css-mendel.it.|StemGen SpA, Milan, Italy.|Dept. of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy.|IRCSS Casa Sollievo della Sofferenza, c/o Instituto Mendel, Rome, Italy.
authors.forename: Angelo L
authors.initials: AL
authors.lastname: Vescovi
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy; D005909:Glioblastoma / Q000473:pathology* / Q000628:therapy; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype; D000071818:Wnt-5a Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C085389:WNT5A protein, human; D000071818:Wnt-5a Protein