title: Plac8 links oncogenic mutations to regulation of autophagy and is critical to pancreatic cancer progression.
abstract: Mutations in p53 and RAS potently cooperate in oncogenic transformation, and correspondingly, these genetic alterations frequently coexist in pancreatic ductal adenocarcinoma (PDA) and other human cancers. Previously, we identified a set of genes synergistically activated by combined RAS and p53 mutations as frequent downstream mediators of tumorigenesis. Here, we show that the synergistically activated gene Plac8 is critical for pancreatic cancer growth. Silencing of Plac8 in cell lines suppresses tumor formation by blocking autophagy, a process essential for maintaining metabolic homeostasis in PDA, and genetic inactivation in an engineered mouse model inhibits PDA progression. We show that Plac8 is a critical regulator of the autophagic machinery, localizing to the lysosomal compartment and facilitating lysosome-autophagosome fusion. Plac8 thus provides a mechanistic link between primary oncogenic mutations and the induction of autophagy, a central mechanism of metabolic reprogramming, during PDA progression.
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Conan
authors.initials: C
authors.lastname: Kinsey
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Balakrishnan
authors.affiliation: Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: O'Dell
authors.affiliation: Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Jing Li
authors.initials: JL
authors.lastname: Huang
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Laurel
authors.initials: L
authors.lastname: Newman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Christa L
authors.initials: CL
authors.lastname: Whitney-Miller
authors.affiliation: Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA; James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. Electronic address: aram_hezel@urmc.rochester.edu.
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA; James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. Electronic address: land@urmc.rochester.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Land
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C506004:PLAC8 protein, human; C475342:Plac8 protein, mouse; D011506:Proteins