Clinical, molecular, metabolic, and immune features associated with oxidative phosphorylation in melanoma brain metastases.
Clinical, molecular, metabolic, and immune features associated with oxidative phosphorylation in melanoma brain metastases.
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DOI：
10.1093/noajnl/vdaa177
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Davies MA
中科院分区：
文献类型：
--
作者：
Fischer GM;Guerrieri RA;Hu Q;Joon AY;Kumar S;Haydu LE;McQuade JL;Vashisht Gopal YN;Knighton B;Deng W;Hudgens CW;Lazar AJ;Tetzlaff MT;Davies MA
最近，我们发现，黑色素瘤脑转移瘤（MBMs）的特点是增加利用氧化磷酸化（OXPHOS）代谢途径相比，黑色素瘤颅外转移瘤（ECM）。MBM的生长被一个有效的直接OXPHOS抑制剂抑制，但观察到的毒性支持需要确定替代治疗策略。因此，我们探讨了与OXPHOS相关的功能，以提高我们对MBMs的发病机制和潜在治疗漏洞的理解。我们将OXPHOS基因签名应用于我们的手术切除的MBM队列，这些MBM已接受RNA测序（RNA-seq）（n = 88）。通过策展基因集的聚类鉴定了具有显著富集（高-OXPHOS; n = 21）和耗竭（低-OXPHOS; n = 25）的OXPHOS基因的MBM。利用临床数据、RNA-seq分析和免疫组织化学来鉴定MBM中与OXPHOS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具有高和低OXPHOS的黑色素瘤，并用于功能验证。与低OXPHOS MBMs相比，高OXPHOS MBMs与开颅手术的生存期较短相关。高-OXPHOS MBM表现出谷氨酰胺代谢的增加，并且用谷氨酰胺酶抑制剂CB 839治疗改善了具有MAPKi抗性、高-OXPHOS颅内异种移植物的小鼠的存活率。高OXPHOS MBM还表现出免疫激活缺陷的转录特征，其在B16-F10颅内肿瘤中用二甲双胍治疗（一种OXPHOS抑制剂）逆转。OXPHOS与MBM中不同的临床、分子、代谢和免疫表型相关。这些协会建议合理的治疗策略，进一步测试，以改善MBM患者的结果。
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) (n = 88). Clustering by curated gene sets identified MBMs with significant enrichment (High-OXPHOS; n = 21) and depletion (Low-OXPHOS; n = 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.
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影响因子：
50.3
作者：
Vazquez F;Lim JH;Chim H;Bhalla K;Girnun G;Pierce K;Clish CB;Granter SR;Widlund HR;Spiegelman BM;Puigserver P
通讯作者：
Puigserver P
影响因子：
4.3
作者：
Cohen JV;Tawbi H;Margolin KA;Amravadi R;Bosenberg M;Brastianos PK;Chiang VL;de Groot J;Glitza IC;Herlyn M;Holmen SL;Jilaveanu LB;Lassman A;Moschos S;Postow MA;Thomas R;Tsiouris JA;Wen P;White RM;Turnham T;Davies MA;Kluger HM
通讯作者：
Kluger HM
DOI：
10.3791/1986
发表时间：
2010-07-13
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Ozawa, Tomoko;James, C David
通讯作者：
James, C David
DOI：
10.1016/s1470-2045(16)30053-5
发表时间：
2016-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Goldberg SB;Gettinger SN;Mahajan A;Chiang AC;Herbst RS;Sznol M;Tsiouris AJ;Cohen J;Vortmeyer A;Jilaveanu L;Yu J;Hegde U;Speaker S;Madura M;Ralabate A;Rivera A;Rowen E;Gerrish H;Yao X;Chiang V;Kluger HM
通讯作者：
Kluger HM
影响因子：
5.7
作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.