Non-metabolic functions of phosphofructokinase-1 orchestrate tumor cellular invasion and genome maintenance under bevacizumab therapy.

Autor:	Lim YC; Danish Cancer Society, Denmark., Jensen KE; Danish Cancer Society, Denmark., Aguilar-Morante D; Danish Cancer Society, Denmark., Vardouli L; Danish Cancer Society, Denmark., Vitting-Seerup K; Danish Cancer Society, Denmark.; Department of Health Technology, Danish Technical University, Denmark., Gimple RC; Department of Medicine, Division of Regenerative Medicine, University of California San Diego, La Jolla, CA, USA., Wu Q; Department of Medicine, Division of Regenerative Medicine, University of California San Diego, La Jolla, CA, USA., Pedersen H; Danish Cancer Society, Denmark., Elbaek KJ; Danish Cancer Society, Denmark., Gromova I; Danish Cancer Society, Denmark., Ihnatko R; Institute of Pathology, University Medical Center, Goettingen University, Germany., Kristensen BW; Department of Pathology, Odense University Hospital, Denmark., Petersen JK; Department of Pathology, Odense University Hospital, Denmark.; Department of Clinical Research, University of Southern Denmark, Denmark., Skjoth-Rasmussen J; Department of Neurosurgery, Copenhagen University Hospital, Denmark., Flavahan W; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Rich JN; Department of Medicine, Division of Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Hamerlik P; Danish Cancer Society, Denmark.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2023 Feb 14; Vol. 25 (2), pp. 248-260.
DOI:	10.1093/neuonc/noac135
Abstrakt:	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. (© 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.)
Databáze:	MEDLINE
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