Mack Stephen C, Agnihotri Sameer, Bertrand Kelsey C, Wang Xin, Shih David J, Witt Hendrik, Hill Nadia, Zayne Kory, Barszczyk Mark, Ramaswamy Vijay, Remke Marc, Thompson Yuan, Ryzhova Marina, Massimi Luca, Grajkowska Wieslawa, Lach Boleslaw, Gupta Nalin, Weiss William A, Guha Abhijit, Hawkins Cynthia, Croul Sidney, Rutka James T, Pfister Stefan M, Korshunov Andrey, Pekmezci Melike, Tihan Tarik, Philips Joanna J, Jabado Nada, Zadeh Gelareh, Taylor Michael D
Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
Clin Cancer Res. 2015 Aug 15;21(16):3750-8. doi: 10.1158/1078-0432.CCR-14-2650. Epub 2015 May 8.
Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy.
Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production.
At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production.
Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.
黏液乳头型室管膜瘤（MPE）是室管膜瘤一种独特的组织学变异型，常见于脊髓。尽管总体预后良好，但已有远处转移、蛛网膜下腔播散和晚期复发的报道。目前，MPE唯一有效的治疗方法是全切除。我们对脊髓室管膜瘤的基因组和转录图谱进行了特征分析，以阐明该疾病的遗传基础并确定新的治疗线索。
对35例脊髓室管膜瘤进行基因表达谱分析，对46例脊髓室管膜瘤的重叠队列进行拷贝数分析。对肿瘤裂解物进行功能验证实验，包括测量丙酮酸激酶M活性（PKM）、己糖激酶活性（HK）和乳酸生成的检测。
在基因表达水平上，我们证明脊髓二级室管膜瘤和MPE在分子和生物学上是不同的。每种组织学变异型中发生的特定拷贝数改变支持了这一点。通路分析显示，MPE的特征是细胞代谢增加，与HIF1α上调有关。蛋白质印迹分析验证了这些发现，表明HIF1α、HK2、PDK1的蛋白表达增加以及PDHE1A的磷酸化增加。对MPE裂解物进行功能检测，结果显示PKM活性降低、HK活性增加和乳酸生成升高。
我们的研究结果表明，MPE可能由瓦氏代谢表型驱动。促进瓦氏表型的关键酶：HK2、PKM2和PDK可被小分子抑制剂/激活剂靶向，应考虑在未来MPE的临床试验中进行评估。
