PDF(Pubmed)
Abstract：
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.
摘要：
恶性周围神经鞘瘤（MPNSTs）是侵袭性肉瘤，可偶尔出现，也可出现在遗传综合征1型神经纤维瘤病（NF1）患者中。预后很糟糕,作为大尺寸，复发的风险，解剖定位使手术效果不佳，没有已知的治疗方法。因此，对MPNST分子特征的鉴定可能以有效和选择性的方式被击中,这对于设想治疗方案是强制性的.这里,我们发现MPNSTs表达高水平的糖酵解酶己糖激酶2（HK2），当癌细胞位于MAMs（线粒体相关膜）时，它可以保护癌细胞免受有害刺激，线粒体与内质网的接触部位。从MAM中去除HK2的HK2靶向肽快速诱导MPNST细胞大量死亡。在鉴定了MPNST微环境中表达的不同基质金属蛋白酶（MMPs）后，我们设计了HK2靶向肽变体，这些变体包含这些MMP的切割位点，使这类肽在癌细胞附近可活化。我们发现携带MMP2/9切割位点的肽是最有效的，既抑制MPNST细胞的体外致瘤性，又阻碍其在小鼠中的生长。我们的数据表明，从MAM中分离HK2可以为新型的抗MPNST治疗策略铺平道路，可以灵活地适应肿瘤微环境的蛋白酶表达特征。
