Pham Khoa, Hanaford Allison R, Poore Brad A, Maxwell Micah J, Sweeney Heather, Parthasarathy Akhila, Alt Jesse, Rais Rana, Slusher Barbara S, Eberhart Charles G, Raabe Eric H
Division of Neuropathology, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
Cancers (Basel). 2022 Mar 3;14(5):1311. doi: 10.3390/cancers14051311.
Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human -amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions-in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, -amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses.
细胞代谢重编程是癌症的一个标志。改变代谢使癌细胞能够克服不利的微环境条件并进行增殖和侵袭。髓母细胞瘤是儿童最常见的恶性脑肿瘤。MYC基因的扩增定义了预后不良的髓母细胞瘤亚群。我们通过比较肿瘤细胞在三种不同条件下（体外、侧腹异种移植和小脑原位异种移植）的代谢谱，对人MYC扩增的髓母细胞瘤进行了全面的代谢研究。主成分分析表明，脑和侧腹高MYC髓母细胞瘤肿瘤的代谢谱紧密聚集在一起，并与正常脑和体外MYC扩增细胞分离。与正常脑相比，MYC扩增的髓母细胞瘤原位异种移植肿瘤显示三羧酸循环以及核苷酸、己糖胺、氨基酸和谷胱甘肽的合成上调。与侧腹异种移植肿瘤和培养中的细胞相比，原位异种移植肿瘤中的葡萄糖摄取和利用明显更高。在原位肿瘤中，葡萄糖是通过三羧酸循环合成谷氨酸、谷氨酰胺和谷胱甘肽的主要碳源。在体内，谷氨酰胺酶II途径是利用谷氨酰胺的主要途径。与正常脑相比，谷胱甘肽是原位肿瘤中上调最丰富的代谢物。谷氨酰胺衍生的谷胱甘肽在体内通过谷氨酰胺转氨酶K（GTK）酶合成。总之，高MYC髓母细胞瘤细胞在体外与体内具有不同的代谢谱，不进行体内代谢分析可能会遗漏关键的脆弱性。
