磷酸果糖激酶-1 的非代谢功能在贝伐单抗治疗下协调肿瘤细胞侵袭和基因组维持。
Non-metabolic functions of phosphofructokinase-1 orchestrate tumor cellular invasion and genome maintenance under bevacizumab therapy.
机构信息
Danish Cancer Society, Denmark.
Department of Health Technology, Danish Technical University, Denmark.
出版信息
Neuro Oncol. 2023 Feb 14;25(2):248-260. doi: 10.1093/neuonc/noac135.
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.
背景
胶质母细胞瘤（GBM）是一种高度致命的恶性肿瘤，新血管生成是其明确的标志。抗血管内皮生长因子（VEGF）抗体贝伐珠单抗已被批准用于治疗复发性 GBM，但普遍存在耐药性。
方法
我们分析了接受贝伐珠单抗治疗的 GBM 患者的表达数据，以发现潜在的耐药机制。通过基因和药物靶向，对患者来源的异种移植物（PDX）和培养物进行研究，以探究磷酸果糖激酶-1，肌肉同工型（PFKM）缺失对肿瘤细胞迁移、运动和侵袭的影响。
结果
我们确定 PFKM 是贝伐珠单抗耐药的驱动因素。PFKM 的功能根据亚细胞位置分为两种：细胞质 PFKM 与管状运动蛋白 KIF11 相互作用，促进肿瘤侵袭，而核 PFKM 通过与 NBS1 相互作用来保护肿瘤细胞的基因组稳定性。利用差异转录谱分析，布比卡因模拟了 PFKM 的基因靶向，增强了贝伐珠单抗在体内临床前 GBM 模型中的疗效。
结论
PFKM 在 GBM 中驱动新的分子途径，为新的治疗范式提供了转化途径。
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