Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors.

Animals Brain Neoplasms / drug therapy Carrier Proteins Cytokines Glioblastoma / genetics Humans Neoplasm Recurrence, Local / pathology Neoplastic Stem Cells / metabolism Positron Emission Tomography Computed Tomography Rats Stem Cells Tumor Microenvironment
glioblastoma pleiotrophin recurrence self-renewal tumor resection

Journal

Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420

Informations de publication

Date de publication:
01 07 2022
Historique:
pubmed: 30 12 2021
medline: 8 7 2022
entrez: 29 12 2021
Statut: ppublish

Résumé

Glioblastomas are highly resistant to therapy, and virtually all patients experience tumor recurrence after standard-of-care treatment. Surgical tumor resection is a cornerstone in glioblastoma therapy, but its impact on cellular phenotypes in the local postsurgical microenvironment has yet to be fully elucidated. We developed a preclinical orthotopic xenograft tumor resection model in rats with integrated 18F-FET PET/CT imaging. Primary and recurrent tumors were subject to bulk and single-cell RNA sequencing. Differentially expressed genes and pathways were investigated and validated using tissue specimens from the xenograft model, 23 patients with matched primary/recurrent tumors, and a cohort including 190 glioblastoma patients. Functional investigations were performed in vitro with multiple patient-derived cell cultures. Tumor resection induced microglia/macrophage infiltration, angiogenesis as well as proliferation and upregulation of several stem cell-related genes in recurrent tumor cells. Expression changes of selected genes SOX2, POU3F2, OLIG2, and NOTCH1 were validated at the protein level in xenografts and early recurrent patient tumors. Single-cell transcriptomics revealed the presence of distinct phenotypic cell clusters in recurrent tumors which deviated from clusters found in primary tumors. Recurrent tumors expressed elevated levels of pleiotrophin (PTN), secreted by both tumor cells and tumor-associated microglia/macrophages. Mechanistically, PTN could induce tumor cell proliferation, self-renewal, and the stem cell program. In glioblastoma patients, high PTN expression was associated with poor overall survival and identified as an independent prognostic factor. Surgical tumor resection is an iatrogenic driver of PTN-mediated self-renewal in glioblastoma tumor cells that promotes therapeutic resistance and tumor recurrence.

Sections du résumé

BACKGROUND
Glioblastomas are highly resistant to therapy, and virtually all patients experience tumor recurrence after standard-of-care treatment. Surgical tumor resection is a cornerstone in glioblastoma therapy, but its impact on cellular phenotypes in the local postsurgical microenvironment has yet to be fully elucidated.
METHODS
We developed a preclinical orthotopic xenograft tumor resection model in rats with integrated 18F-FET PET/CT imaging. Primary and recurrent tumors were subject to bulk and single-cell RNA sequencing. Differentially expressed genes and pathways were investigated and validated using tissue specimens from the xenograft model, 23 patients with matched primary/recurrent tumors, and a cohort including 190 glioblastoma patients. Functional investigations were performed in vitro with multiple patient-derived cell cultures.
RESULTS
Tumor resection induced microglia/macrophage infiltration, angiogenesis as well as proliferation and upregulation of several stem cell-related genes in recurrent tumor cells. Expression changes of selected genes SOX2, POU3F2, OLIG2, and NOTCH1 were validated at the protein level in xenografts and early recurrent patient tumors. Single-cell transcriptomics revealed the presence of distinct phenotypic cell clusters in recurrent tumors which deviated from clusters found in primary tumors. Recurrent tumors expressed elevated levels of pleiotrophin (PTN), secreted by both tumor cells and tumor-associated microglia/macrophages. Mechanistically, PTN could induce tumor cell proliferation, self-renewal, and the stem cell program. In glioblastoma patients, high PTN expression was associated with poor overall survival and identified as an independent prognostic factor.
CONCLUSION
Surgical tumor resection is an iatrogenic driver of PTN-mediated self-renewal in glioblastoma tumor cells that promotes therapeutic resistance and tumor recurrence.

Identifiants

DOI: 10.1093/neuonc/noab302 PMID: 34964899 PMC: PMC9248408
pubmed: 34964899
pii: 6489042
doi: 10.1093/neuonc/noab302
pmc: PMC9248408
doi:

Substances chimiques

Carrier Proteins 0
Cytokines 0
pleiotrophin 134034-50-7

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1074-1087

Commentaires et corrections

Type : CommentIn

Informations de copyright

© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Références

J Immunol Methods. 2009 Aug 15;347(1-2):70-8
pubmed: 19567251
Cell Stem Cell. 2018 Sep 6;23(3):370-381.e5
pubmed: 30100167
Sci Rep. 2020 Jun 9;10(1):9285
pubmed: 32518380
Clin Cancer Res. 2021 Apr 1;27(7):2038-2049
pubmed: 33542075
Nat Cancer. 2021 Feb;2(2):157-173
pubmed: 35122077
Neuro Oncol. 2018 Jan 22;20(2):236-248
pubmed: 29016925
Lancet Oncol. 2009 May;10(5):459-66
pubmed: 19269895
Lab Anim Res. 2018 Dec;34(4):248-256
pubmed: 30671112
J Neurooncol. 2013 Jan;111(1):19-23
pubmed: 23054563
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Genes Dev. 2019 Jun 1;33(11-12):591-609
pubmed: 31160393
J Clin Invest. 2017 Feb 1;127(2):415-426
pubmed: 28145904
Am J Transl Res. 2019 Oct 15;11(10):6393-6402
pubmed: 31737191
Ann Oncol. 2008 Nov;19(11):1821-8
pubmed: 18550576
PLoS One. 2015 Feb 13;10(2):e0115315
pubmed: 25680186
Front Pharmacol. 2020 Mar 27;11:358
pubmed: 32292341
Front Biosci. 2008 May 01;13:3793-7
pubmed: 18508474
Neuro Oncol. 2016 Dec;18(12):1622-1633
pubmed: 27298311
Neuro Oncol. 2015 Oct;17(10):1322-32
pubmed: 26203067
J Neurooncol. 2016 May;128(1):1-8
pubmed: 26961772
Nucleic Acids Res. 2011 Jan;39(Database issue):D691-7
pubmed: 21067998
Neuro Oncol. 2016 Dec;18(12):1688-1689
pubmed: 27765836
Cell. 2014 Apr 24;157(3):580-94
pubmed: 24726434
Nat Commun. 2017 Jun 01;8:15080
pubmed: 28569747
J Clin Invest. 2020 Jan 2;130(1):315-328
pubmed: 31613796
Stem Cells. 2017 Nov;35(11):2218-2228
pubmed: 28895245
Oncotarget. 2017 Feb 14;8(7):12145-12157
pubmed: 28076333
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Nucleic Acids Res. 2016 Jan 4;44(D1):D457-62
pubmed: 26476454
Neuron. 2014 Jan 22;81(2):229-48
pubmed: 24462092
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
Br J Pharmacol. 2016 Feb;173(4):692-702
pubmed: 25752446
Database (Oxford). 2016 Jul 03;2016:
pubmed: 27374120
Signal Transduct Target Ther. 2021 Mar 23;6(1):124
pubmed: 33753720
JAMA Oncol. 2016 Nov 01;2(11):1460-1469
pubmed: 27310651
Genes Dev. 2015 Jun 15;29(12):1203-17
pubmed: 26109046

Auteurs

Arnon Møldrup Knudsen (AM)

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Pathology, Odense University Hospital, Odense, Denmark.
ORCID: 0000-0003-0191-1714

Bo Halle (B)

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Neurosurgery, Odense University Hospital, Odense, Denmark.

Oriane Cédile (O)

Hematology-Pathology Research Laboratory, Research Unit for Hematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, Odense, Denmark.

Mark Burton (M)

Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Clinical Genome Center, University of Southern Denmark & Region of Southern Denmark, Odense, Denmark.

Christina Baun (C)

Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
Danish Molecular Biomedical Imaging Center (DaMBIC), University of Southern Denmark, Odense, Denmark.

Helge Thisgaard (H)

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.

Atul Anand (A)

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Pathology, Odense University Hospital, Odense, Denmark.

Christopher Hubert (C)

Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.

Mads Thomassen (M)

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Clinical Genome Center, University of Southern Denmark & Region of Southern Denmark, Odense, Denmark.

Signe Regner Michaelsen (SR)

Department of Pathology, Bartholin Institute, Copenhagen University Hospital, Copenhagen, Denmark.

Birgitte Brinkmann Olsen (BB)

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.

Rikke Hedegaard Dahlrot (RH)

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Oncology, Odense University Hospital, Odense, Denmark.

Rolf Bjerkvig (R)

Department of Biomedicine, University of Bergen, Bergen, Norway.
NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg.

Justin Durla Lathia (JD)

Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA.

Bjarne Winther Kristensen (BW)

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Pathology, Odense University Hospital, Odense, Denmark.
Department of Pathology, Bartholin Institute, Copenhagen University Hospital, Copenhagen, Denmark.
Department of Clinical Medicine and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de transport › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › Astrocytome › Glioblastome › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Surgical resection of glioblastomas induces...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches tumorales › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Techniques de diagnostic radioisotopique › Scintigraphie › Tomoscintigraphie › Tomographie par émission de positons › Tomographie par émission de positons couplée à la tomodensitométrie › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Cellules › Cellules souches › Surgical resection of glioblastomas induces...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Surgical resection of glioblastomas induces...