Non-metabolic functions of phosphofructokinase-1 orchestrate tumor cellular invasion and genome maintenance under bevacizumab therapy. Issue 2 (24th May 2022)

• Record Type: Journal Article
• Authors: Lim, Yi Chieh; Jensen, Kamilla E; Aguilar-Morante, Diana; Vardouli, Lina; Vitting-Seerup, Kristoffer; Gimple, Ryan C; Wu, Qiulian; Pedersen, Henriette; Elbaek, Kirstine J; Gromova, Irina; Ihnatko, Robert; Kristensen, Bjarne W; Petersen, Jeanette K; Skjoth-Rasmussen, Jane; Flavahan, William; Rich, Jeremy N; Hamerlik, Petra
• Is Part Of: Neuro-oncology. Volume 25:Issue 2(2023)
• Page Start: 248
• Page End: 260
• Publication Date: 2022-05-24
• Subjects: bevacizumab -- DNA damage and repair -- invasion -- PFKM; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac135
• Languages: English
• ISSNs: 1522-8517

Abstract

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. Graphical Abstract: