Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas,Science Translational Medicine

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Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas
Science Translational Medicine ( IF 15.8 ) Pub Date : 2021-10-06 , DOI: 10.1126/scitranslmed.abc0497
Pooja Panwalkar ₁ , Benita Tamrazi ₂ , Derek Dang ₁ , Chan Chung ₃ , Stefan Sweha ₁ , Siva Kumar Natarajan ₁ , Matthew Pun ₁ , Jill Bayliss ₁ , Martin P Ogrodzinski _{4,

5} , Drew Pratt ₁ , Brendan Mullan ₆ , Debra Hawes ₇ , Fusheng Yang ₇ , Chao Lu ₈ , Benjamin R Sabari ₉ , Abhinav Achreja _{10,

11} , Jin Heon _{10,

11} , Olamide Animasahun _{10,

11,

12} , Marcin Cieslik ₁ , Christopher Dunham _{13,

14} , Stephen Yip ₁₄ , Juliette Hukin ₁₅ , Joanna J Phillips _{16,

17} , Miriam Bornhorst _{18,

19} , Andrea M Griesinger _{20,

21} , Andrew M Donson _{20,

21} , Nicholas K Foreman _{21,

22} , Hugh J L Garton ₂₂ , Jason Heth ₂₂ , Karin Muraszko ₂₂ , Javad Nazarian _{18,

19,

23} , Carl Koschmann ₆ , Li Jiang ₂₄ , Mariella G Filbin ₂₄ , Deepak Nagrath _{10,

11} , Marcel Kool _{25,

26,

27} , Andrey Korshunov ₂₈ , Stefan M Pfister _{25,

26,

29} , Richard J Gilbertson ₃₀ , C David Allis ₉ , Arul M Chinnaiyan ₁ , Sophia Y Lunt _{4,

31} , Stefan Blüml ₂ , Alexander R Judkins ₇ , Sriram Venneti _{1,

6}

Affiliation

Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine University of Southern California, Los Angeles, CA 90027, USA.
Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea.
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Department of Pediatrics, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine University of Southern California, Los Angeles, CA 90027, USA.
Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, NY 10065, USA.
Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
Division of Anatomic Pathology, British Columbia Children's Hospital, Vancouver, British Columbia V6H 3N1, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Division of Hematology and Oncology, Children's and Women's Health Centre of B.C., University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.
Department of Pathology, University of California San Francisco, San Francisco, CA 94132, USA.
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94132, USA.
Research Center for Genetic Medicine, Children's National Health System, Washington, DC 20012, USA.
Brain Tumor Institute, Children's National Health System, Washington, DC 20012, USA.
Department of Pediatrics, University of Colorado, Denver, Aurora, CO 80045, USA.
Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO 80045, USA.
Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA.
DMG Research Center, Department of Oncology, University Children's Hospital, CH-8032 Zürich, Switzerland.
Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
Hopp Children's Cancer Center (KiTZ), Heidelberg 69120, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
Princess Máxima Center for Pediatric Oncology, Utrecht 3584, Netherlands.
Department of Neuropathology, German Cancer Research Center (DKFZ), University Hospital Heidelberg and CCU Neuropathology, Heidelberg 69120, Germany.
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany.
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824, USA.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

中文翻译：

靶向致死性儿童 PFA 室管膜瘤中的综合表观遗传和代谢途径

与 B 组室管膜瘤 (PFB) 相比，儿童后颅窝 A 组室管膜瘤 (PFAs) 的治疗选择有限，且预后较差。 PFA 过度表达肿瘤组蛋白样蛋白 EZHIP（Zeste 同源物抑制蛋白的增强子），导致抑制性组蛋白 H3 赖氨酸 27 三甲基化 (H3K27me3) 整体减少，与肿瘤组蛋白 H3K27M 类似。对患者来源的细胞和肿瘤的综合代谢分析、肿瘤的单细胞 RNA 测序以及患者的无创代谢成像表明 PFA 中的糖酵解和三羧酸 (TCA) 循环代谢增强。此外，PFA 中糖酵解基因的高表达与不良结果相关。 PFA 表现出高 EZHIP 表达与不良预后和激活标记组蛋白 H3 赖氨酸 27 乙酰化 (H3K27ac) 升高相关。基因组 H3K27ac 在关键糖酵解和 TCA 循环相关基因（包括己糖激酶 2和丙酮酸脱氢酶）处富含 PFA。同样，表达野生型 EZHIP (EZHIP-WT) 的小鼠神经元干细胞 (NSC) 与催化减弱的 EZHIP-M406K 相比，在己糖激酶 2和丙酮酸脱氢酶上表现出 H3K27ac 富集，同时糖酵解和 TCA 循环代谢增强。 AMPK α -2是代谢调节剂 AMP 激活蛋白激酶 (AMPK) 的关键组成部分，在 PFA 和 EZHIP-WT NSC 中也显示出 H3K27ac 富集。 AMPK 激活剂二甲双胍可降低 EZHIP 蛋白浓度、增加 H3K27me3、抑制 TCA 循环代谢，并在小鼠体内和患者来源的 PFA 异种移植物中显示出体外和体内治疗功效。我们的数据表明，表达 PFA 和 EZHIP-WT 的 NSC 的特点是糖酵解和 TCA 循环代谢增强。重新利用抗糖尿病药物二甲双胍可降低致病性 EZHIP、增加 H3K27me3 并抑制肿瘤生长，这表明针对综合代谢/表观遗传途径是治疗儿童室管膜瘤的潜在治疗策略。

更新日期：2021-10-06

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