title: Nuclear inclusion bodies of mutant and wild-type p53 in cancer: a hallmark of p53 inactivation and proteostasis remodelling by p53 aggregation.
abstract: Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies, and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers, and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders. In cell culture, tumour-associated stress was a strong inducer of p53 aggregation and nIB formation. This was most prominent for mutant p53, but could also be observed in wild-type p53 cell lines, for which nIB formation correlated with the loss of p53's transcriptional activity. Importantly, protein aggregation also fuelled the dysregulation of the proteostasis network in the tumour cell by inducing a hyperactivated, oncogenic heat-shock response, to which tumours are commonly addicted, and by overloading the proteasomal degradation system, an observation that was most pronounced for structurally destabilized mutant p53. Patients showing tumours with p53-positive nIBs suffered from a poor clinical outcome, similar to those with loss of p53 expression, and tumour biopsies showed a differential proteostatic expression profile associated with p53-positive nIBs. p53-positive nIBs therefore highlight a malignant state of the tumour that results from the interplay between (1) the functional inactivation of p53 through mutation and/or aggregation, and (2) microenvironmental stress, a combination that catalyses proteostatic dysregulation. This study highlights several unexpected clinical, biological and therapeutically unexplored parallels between cancer and neurodegeneration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.|Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.|The Broad Institute, Cambridge, MA, USA.
authors.forename: Frederik
authors.initials: F
authors.lastname: De Smet
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Mirian
authors.initials: M
authors.lastname: Saiz Rubio
authors.affiliation: Department of Abdominal Surgery, University Hospitals Gasthuisberg, Leuven, Belgium.
authors.forename: Daphne
authors.initials: D
authors.lastname: Hompes
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Naus
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: De Baets
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Tobias
authors.initials: T
authors.lastname: Langenberg
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hipp
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Houben
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Claes
authors.affiliation: Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Charbonneau
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Javier
authors.initials: J
authors.lastname: Delgado Blanco
authors.affiliation: Nucleomics Core, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
authors.forename: Stephane
authors.initials: S
authors.lastname: Plaisance
authors.affiliation: Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Children's Hospital Boston, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Boston, MA, USA.
authors.forename: Shakti
authors.initials: S
authors.lastname: Ramkissoon
authors.affiliation: Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Ramkissoon
authors.affiliation: Department of Epidemiology - GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Colinda
authors.initials: C
authors.lastname: Simons
authors.affiliation: Department of Epidemiology - GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Piet
authors.initials: P
authors.lastname: van den Brandt
authors.affiliation: Department of Epidemiology - GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Matty
authors.initials: M
authors.lastname: Weijenberg
authors.affiliation: Department of Pathology - GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Manon
authors.initials: M
authors.lastname: Van England
authors.affiliation: Department of Obstetrics and Gynaecology, Division of Gynaecological Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Lambrechts
authors.affiliation: Department of Obstetrics and Gynaecology, Division of Gynaecological Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.|Centre for Gynaecological Oncology Amsterdam, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Frederic
authors.initials: F
authors.lastname: Amant
authors.affiliation: Department of Abdominal Surgery, University Hospitals Gasthuisberg, Leuven, Belgium.
authors.forename: André
authors.initials: A
authors.lastname: D'Hoore
authors.affiliation: Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.|The Broad Institute, Cambridge, MA, USA.|Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Children's Hospital Boston, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Boston, MA, USA.|Department of Pathology, Children's Hospital Boston, Boston, MA, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.affiliation: The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.|VIB Center for Brain and Disease Research, Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
mesh_terms: D001706:Biopsy; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D005909:Glioblastoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018869:Heat-Shock Response / Q000235:genetics / Q000502:physiology; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D009154:Mutation; D066263:Protein Aggregation, Pathological / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D017480:Receptors, sigma; D016159:Tumor Suppressor Protein p53
keywords: colon cancer; glioblastoma; nuclear inclusion bodies; p53 aggregation; proteostasis