Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Helsinki University Lipidomics Unit, Helsinki Institute of Life Science (HiLIFE) and Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland.
EMBO Mol Med. 2019 Jun;11(6). doi: 10.15252/emmm.201809034.
The current clinical care of glioblastomas leaves behind invasive, radio- and chemo-resistant cells. We recently identified mammary-derived growth inhibitor (MDGI/) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient-derived glioma cells via lysosomal membrane permeabilization (LMP). In a preclinical model, treatment of glioma-bearing mice with an antihistaminergic LMP-inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re-positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo-resistant glioma cells from sustaining disease progression and recurrence.
目前胶质母细胞瘤的临床治疗方法会留下侵袭性、放射性和化学抗性细胞。我们最近发现乳腺衍生生长抑制剂（MDGI/）是侵袭性神经胶质瘤的生物标志物。在这里，我们证明了 MDGI 在维持溶酶体膜完整性方面的新功能，从而使侵袭性神经胶质瘤细胞对溶酶体膜不稳定异常敏感。MDGI 沉默会损害多不饱和脂肪酸进入细胞的运输，导致溶酶体膜脂质组成发生重大变化，随后通过溶酶体膜通透性（LMP）导致患者来源的神经胶质瘤细胞死亡。在临床前模型中，用一种抗组胺 LMP 诱导药物治疗携带神经胶质瘤的小鼠，可有效清除侵袭性神经胶质瘤细胞和大脑内的继发性肿瘤。这种侵袭性浸润细胞对 LMP 的意外脆弱性为临床干预提供了新的机会，例如重新定位一种已有的抗组胺药物，以根除无法手术、侵袭性和化学抗性的神经胶质瘤细胞，从而阻止疾病的进展和复发。
