title: Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition.
abstract: High-grade serous ovarian carcinoma (HGS-OvCa) harbors p53 mutations and can originate from the epithelial cell compartment of the fallopian tube fimbriae. From this site, neoplastic cells detach, survive in the peritoneal cavity, and form cellular clusters that intercalate into the mesothelium to form ovarian and peritoneal masses. To examine the contribution of mutant p53 to phenotypic alterations associated with HGS-OvCA, we developed live-cell microscopy assays that recapitulate these early events in cultured fallopian tube nonciliated epithelial (FNE) cells. Expression of stabilizing mutant variants of p53, but not depletion of endogenous wild-type p53, in FNE cells promoted survival and cell-cell aggregation under conditions of cell detachment, leading to the formation of cell clusters with mesothelium-intercalation capacity. Mutant p53R175H-induced phenotypes were dependent on fibronectin production, α5β1 fibronectin receptor engagement, andTWIST1expression. These results indicate that FNE cells expressing stabilizing p53 mutants acquire anchorage independence and subsequent mesothelial intercalation capacity through a mechanism involving mesenchymal transition and matrix production. These findings provide important new insights into activities of mutant p53 in the cells of origin of HGS-OvCa.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Iwanicki
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hsing-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Iavarone
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ioannis K
authors.initials: IK
authors.lastname: Zervantonakis
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Taru
authors.initials: T
authors.lastname: Muranen
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Center for Molecular Oncologic Pathology, Boston, Massachusetts, USA.
authors.forename: Marián
authors.initials: M
authors.lastname: Novak
authors.affiliation: Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Tan A
authors.initials: TA
authors.lastname: Ince
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Center for Molecular Oncologic Pathology, Boston, Massachusetts, USA.|Penn Ovarian Cancer Research Center, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge