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

Yi Chieh Lim, Kamilla E Jensen, Diana Aguilar-Morante, Lina Vardouli, Kristoffer Vitting-Seerup, Ryan C Gimple, Qiulian Wu, Henriette Pedersen, Kirstine J Elbaek, Irina Gromova, Robert Ihnatko, Bjarne W Kristensen, Jeanette K Petersen, Jane Skjoth-Rasmussen, William Flavahan, Jeremy N Rich, Petra Hamerlik

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalNeuro-Oncology
Volume25
Issue number2
Pages (from-to)248-260
ISSN1522-8517
DOIs
Publication statusPublished - 14. Feb 2023

Keywords

  • DNA damage and repair
  • PFKM
  • bevacizumab
  • invasion
  • Bevacizumab/pharmacology
  • Glioblastoma/drug therapy
  • Phosphofructokinase-1
  • Humans
  • Brain Neoplasms/drug therapy

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