Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors
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Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors. / Knudsen, Arnon Møldrup; Halle, Bo; Cédile, Oriane; Burton, Mark; Baun, Christina; Thisgaard, Helge; Anand, Atul; Hubert, Christopher; Thomassen, Mads; Michaelsen, Signe Regner; Olsen, Birgitte Brinkmann; Dahlrot, Rikke Hedegaard; Bjerkvig, Rolf; Lathia, Justin Durla; Kristensen, Bjarne Winther.
In: Neuro-Oncology, Vol. 24, No. 7, 2022, p. 1074-1087.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors
AU - Knudsen, Arnon Møldrup
AU - Halle, Bo
AU - Cédile, Oriane
AU - Burton, Mark
AU - Baun, Christina
AU - Thisgaard, Helge
AU - Anand, Atul
AU - Hubert, Christopher
AU - Thomassen, Mads
AU - Michaelsen, Signe Regner
AU - Olsen, Birgitte Brinkmann
AU - Dahlrot, Rikke Hedegaard
AU - Bjerkvig, Rolf
AU - Lathia, Justin Durla
AU - Kristensen, Bjarne Winther
N1 - Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - glioblastoma
KW - pleiotrophin
KW - recurrence
KW - self-renewal
KW - tumor resection
U2 - 10.1093/neuonc/noab302
DO - 10.1093/neuonc/noab302
M3 - Journal article
C2 - 34964899
AN - SCOPUS:85133956550
VL - 24
SP - 1074
EP - 1087
JO - Neuro-Oncology
JF - Neuro-Oncology
SN - 1522-8517
IS - 7
ER -
ID: 314837383