Fischer Grant M, Guerrieri Renato A, Hu Qianghua, Joon Aron Y, Kumar Swaminathan, Haydu Lauren E, McQuade Jennifer L, Vashisht Gopal Y N, Knighton Barbara, Deng Wanleng, Hudgens Courtney W, Lazar Alexander J, Tetzlaff Michael T, Davies Michael A
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Neurooncol Adv. 2021 Jan 6;3(1):vdaa177. doi: 10.1093/noajnl/vdaa177. eCollection 2021 Jan-Dec.
Recently, we showed that melanoma brain metastases (MBMs) are characterized by increased utilization of the oxidative phosphorylation (OXPHOS) metabolic pathway compared to melanoma extracranial metastases (ECMs). MBM growth was inhibited by a potent direct OXPHOS inhibitor, but observed toxicities support the need to identify alternative therapeutic strategies. Thus, we explored the features associated with OXPHOS to improve our understanding of the pathogenesis and potential therapeutic vulnerabilities of MBMs.
We applied an OXPHOS gene signature to our cohort of surgically resected MBMs that had undergone RNA-sequencing (RNA-seq) ( = 88). Clustering by curated gene sets identified MBMs with significant enrichment (High-OXPHOS; = 21) and depletion (Low-OXPHOS; = 25) of OXPHOS genes. Clinical data, RNA-seq analysis, and immunohistochemistry were utilized to identify significant clinical, molecular, metabolic, and immune associations with OXPHOS in MBMs. Preclinical models were used to further compare melanomas with High- and Low-OXPHOS and for functional validation.
High-OXPHOS MBMs were associated with shorter survival from craniotomy compared to Low-OXPHOS MBMs. High-OXPHOS MBMs exhibited an increase in glutamine metabolism, and treatment with the glutaminase inhibitor CB839 improved survival in mice with MAPKi-resistant, High-OXPHOS intracranial xenografts. High-OXPHOS MBMs also exhibited a transcriptional signature of deficient immune activation, which was reversed in B16-F10 intracranial tumors with metformin treatment, an OXPHOS inhibitor.
OXPHOS is associated with distinct clinical, molecular, metabolic, and immune phenotypes in MBMs. These associations suggest rational therapeutic strategies for further testing to improve outcomes in MBM patients.
最近，我们发现与黑色素瘤颅外转移灶（ECM）相比，黑色素瘤脑转移灶（MBM）的特征在于氧化磷酸化（OXPHOS）代谢途径的利用率增加。一种有效的直接OXPHOS抑制剂可抑制MBM生长，但观察到的毒性表明需要确定替代治疗策略。因此，我们探索了与OXPHOS相关的特征，以增进对MBM发病机制和潜在治疗弱点的理解。
我们将OXPHOS基因特征应用于我们一组接受过手术切除且已进行RNA测序（RNA-seq）的MBM（n = 88）。通过精心策划的基因集进行聚类，确定了OXPHOS基因显著富集（高OXPHOS；n = 21）和耗竭（低OXPHOS；n = 25）的MBM。利用临床数据、RNA-seq分析和免疫组织化学来确定MBM中与OXPHOS相关的显著临床、分子、代谢和免疫关联。临床前模型用于进一步比较高OXPHOS和低OXPHOS黑色素瘤，并进行功能验证。
与低OXPHOS MBM相比，高OXPHOS MBM与开颅术后生存期较短相关。高OXPHOS MBM的谷氨酰胺代谢增加，用谷氨酰胺酶抑制剂CB839治疗可提高对MAPKi耐药的高OXPHOS颅内异种移植小鼠的生存率。高OXPHOS MBM还表现出免疫激活不足的转录特征，在用OXPHOS抑制剂二甲双胍治疗的B16-F10颅内肿瘤中这种特征得到逆转。
OXPHOS与MBM中不同的临床、分子、代谢和免疫表型相关。这些关联提示了合理的治疗策略，有待进一步测试以改善MBM患者的预后。
