Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
J Biol Chem. 2021 Jan-Jun;296:100157. doi: 10.1074/jbc.RA120.014960. Epub 2020 Dec 9.
Meningiomas (MNs), arising from the arachnoid/meningeal layer, are nonresponsive to chemotherapies, with ∼50% showing loss of the Neurofibromatosis 2 (NF2) tumor suppressor gene. Previously, we established NF2 loss activates mechanistic target of rapamycin complex 1 (mTORC1) and mechanistic target of rapamycin complex 2 (mTORC2) signaling, leading to clinical trials for NF2 and MN. Recently our omics studies identified activated ephrin (EPH) receptor and Src family kinases upon NF2 loss. Here, we report increased expression of several ligands in NF2-null human arachnoidal cells (ACs) and the MN cell line Ben-Men-1, particularly neuregulin-1/heregulin (NRG1), and confirm increased NRG1 secretion and activation of V-ERB-B avian erythroblastic leukemia viral oncogene homolog 3 (ERBB3) receptor kinase. Conditioned-medium from NF2-null ACs or exogenous NRG1 stimulated ERBB3, EPHA2, and mTORC1/2 signaling, suggesting pathway crosstalk. NF2-null cells treated with an ERBB3-neutralizing antibody partially downregulated mTOR pathway activation but showed no effect on viability. mTORC1/2 inhibitor treatment decreased NRG1 expression and downregulated ERBB3 while re-activating pAkt T308, suggesting a mechanism independent of NRG1-ERBB3 but likely involving activation of another upstream receptor kinase. Transcriptomics after mTORC1/2 inhibition confirmed decreased ERBB3/ERBB4 while revealing increased expression of insulin-like growth factor receptor 1 (IGF1R). Drug treatment co-targeting mTORC1/2 and IGF1R/insulin receptor attenuated pAkt T308 and showed synergistic effects on viability. Our findings indicate potential autocrine signaling where NF2 loss leads to secretion/activation of NRG1-ERBB3 signaling. mTORC1/2 inhibition downregulates NRG1-ERBB3, while upregulating pAkt T308 through an adaptive response involving IGF1R/insulin receptor and co-targeting these pathways may prove effective for treatment of NF2-deficient MN.
脑膜瘤（MNs）起源于蛛网膜/脑膜层，对化疗无反应，约 50%的脑膜瘤表现出神经纤维瘤病 2 型（NF2）肿瘤抑制基因的缺失。此前，我们已经确定 NF2 的缺失会激活雷帕霉素靶蛋白复合物 1（mTORC1）和雷帕霉素靶蛋白复合物 2（mTORC2）信号通路，这导致了 NF2 和 MN 的临床试验。最近，我们的组学研究发现 NF2 缺失后，Eph 受体和Src 家族激酶被激活。在这里，我们报告 NF2 缺失的人蛛网膜细胞（ACs）和 MN 细胞系 Ben-Men-1 中几种配体的表达增加，特别是神经调节蛋白 1/神经调节蛋白 1（NRG1），并证实 NF2 缺失的 ACs 或外源性 NRG1 分泌增加和 V-ERB-B 禽红细胞白血病病毒癌基因同源物 3（ERBB3）受体激酶激活。NF2 缺失细胞的条件培养基或外源性 NRG1 可刺激 ERBB3、EPH A2 和 mTORC1/2 信号通路，表明通路串扰。用 ERBB3 中和抗体处理 NF2 缺失细胞可部分下调 mTOR 通路激活，但对细胞活力无影响。mTORC1/2 抑制剂治疗降低了 NRG1 的表达并下调了 ERBB3，同时重新激活了 pAkt T308，这表明一种不依赖于 NRG1-ERBB3 的机制，但可能涉及另一种上游受体激酶的激活。mTORC1/2 抑制后的转录组学证实 ERBB3/ERBB4 表达减少，同时胰岛素样生长因子受体 1（IGF1R）表达增加。同时靶向 mTORC1/2 和 IGF1R/胰岛素受体的药物治疗可抑制 pAkt T308，并对细胞活力产生协同作用。我们的研究结果表明，NF2 缺失可能导致 NRG1-ERBB3 信号通路的自分泌信号转导。mTORC1/2 抑制通过涉及 IGF1R/胰岛素受体的适应性反应下调 NRG1-ERBB3，同时上调 pAkt T308，同时靶向这些通路可能对 NF2 缺陷型 MN 的治疗有效。
