Non-metabolic functions of phosphofructokinase-1 orchestrate tumor cellular invasion and genome maintenance under bevacizumab therapy.
DNA damage and repair
PFKM
bevacizumab
invasion
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
14 02 2023
14 02 2023
Historique:
pubmed:
25
5
2022
medline:
16
2
2023
entrez:
24
5
2022
Statut:
ppublish
Résumé
Glioblastoma (GBM) is a highly lethal malignancy for which neoangiogenesis serves as a defining hallmark. The anti-VEGF antibody, bevacizumab, has been approved for the treatment of recurrent GBM, but resistance is universal. We analyzed expression data of GBM patients treated with bevacizumab to discover potential resistance mechanisms. Patient-derived xenografts (PDXs) and cultures were interrogated for effects of phosphofructokinase-1, muscle isoform (PFKM) loss on tumor cell motility, migration, and invasion through genetic and pharmacologic targeting. We identified PFKM as a driver of bevacizumab resistance. PFKM functions dichotomize based on subcellular location: cytosolic PFKM interacted with KIF11, a tubular motor protein, to promote tumor invasion, whereas nuclear PFKM safeguarded genomic stability of tumor cells through interaction with NBS1. Leveraging differential transcriptional profiling, bupivacaine phenocopied genetic targeting of PFKM, and enhanced efficacy of bevacizumab in preclinical GBM models in vivo. PFKM drives novel molecular pathways in GBM, offering a translational path to a novel therapeutic paradigm.
Sections du résumé
BACKGROUND
Glioblastoma (GBM) is a highly lethal malignancy for which neoangiogenesis serves as a defining hallmark. The anti-VEGF antibody, bevacizumab, has been approved for the treatment of recurrent GBM, but resistance is universal.
METHODS
We analyzed expression data of GBM patients treated with bevacizumab to discover potential resistance mechanisms. Patient-derived xenografts (PDXs) and cultures were interrogated for effects of phosphofructokinase-1, muscle isoform (PFKM) loss on tumor cell motility, migration, and invasion through genetic and pharmacologic targeting.
RESULTS
We identified PFKM as a driver of bevacizumab resistance. PFKM functions dichotomize based on subcellular location: cytosolic PFKM interacted with KIF11, a tubular motor protein, to promote tumor invasion, whereas nuclear PFKM safeguarded genomic stability of tumor cells through interaction with NBS1. Leveraging differential transcriptional profiling, bupivacaine phenocopied genetic targeting of PFKM, and enhanced efficacy of bevacizumab in preclinical GBM models in vivo.
CONCLUSION
PFKM drives novel molecular pathways in GBM, offering a translational path to a novel therapeutic paradigm.
Identifiants
pubmed: 35608632
pii: 6591318
doi: 10.1093/neuonc/noac135
pmc: PMC9925708
doi:
Substances chimiques
Bevacizumab
2S9ZZM9Q9V
Phosphofructokinase-1
EC 2.7.1.11
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
248-260Subventions
Organisme : NINDS NIH HHS
ID : R01 NS103434
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA238662
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA217065
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197718
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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