Temozolomide Treatment Increases Fatty Acid Uptake in Glioblastoma Stem Cells.
Temozolomide Treatment Increases Fatty Acid Uptake in Glioblastoma Stem Cells.
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DOI：
10.3390/cancers12113126
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发表时间：
2020-10-26
期刊：
影响因子：
5.2
通讯作者：
Ahmed AU
中科院分区：
文献类型：
--
作者：
Caragher S;Miska J;Shireman J;Park CH;Muroski M;Lesniak MS;Ahmed AU
诊断为胶质母细胞瘤（GBM）脑肿瘤的患者通常存活不到两年，尽管有手术，放疗和化疗的积极治疗。这种致命性的一个主要因素是GBM肿瘤适应压力（包括治疗压力）的能力。代谢在这一过程中的作用仍不完全清楚。因此，我们探讨了GBM中细胞表型、化疗应激和代谢之间的联系。我们发现，诱导GBM表型的变化导致代谢行为的改变。此外，在化疗治疗期间，对治疗产生抗性的GBM细胞增加了它们的脂肪酸摄取。这些治疗引起的营养摄取的改变可能是治疗抵抗和致命复发的基础。在所有癌症中，胶质母细胞瘤（GBM）仍然是最难治疗的癌症之一。这种耐药性的一个关键因素是称为胶质瘤干细胞（GSC）的肿瘤细胞亚群。这些细胞对目前的治疗方式具有高度抗性，具有显著的自我更新能力，被认为是肿瘤复发的关键驱动因素。进一步复杂的GBM的理解，证据表明，GSC群体是不是一个预定的和静态的细胞群，但也包括先前分化的GBM细胞，已达到GSC状态继发于环境的线索。经历可塑性的GBM细胞的代谢行为仍然不完全清楚。为此，我们探索了GSC，环境线索和代谢之间的联系。使用患者来源的异种移植细胞，小鼠模型，转录组学和代谢分析，我们发现细胞状态的变化伴随着代谢表型的急剧变化。此外，用替莫唑胺（目前的GBM标准治疗药物）治疗改变了GBM细胞的代谢，并在可塑性驱动的GSC群体中增加了体外和体内的脂肪酸摄取。这些结果表明，替莫唑胺诱导的细胞状态的变化伴随着代谢的转变-一个潜在的新的目标，以提高目前的治疗方式的有效性。
Patients diagnosed with glioblastoma (GBM) brain tumors typically survive less than two years, despite aggressive therapy with surgery, radiation, and chemotherapy. A major factor underlying this lethality is the ability of GBM tumors to adapt to stress, including the stress of treatment. The role of metabolism in this process remains incompletely understood. We, therefore, explored the connection between cellular phenotype, chemotherapeutic stress, and metabolism in GBM. We found that inducing changes in GBM phenotypes led to alterations in metabolic behavior. Further, during treatment with chemotherapy, GBM cells that became resistant to therapy increased their fatty acid uptake. These therapy-induced alterations in nutrient uptake may underlie therapy resistance and deadly recurrence. Among all cancers, glioblastoma (GBM) remains one of the least treatable. One key factor in this resistance is a subpopulation of tumor cells termed glioma stem cells (GSCs). These cells are highly resistant to current treatment modalities, possess marked self-renewal capacity, and are considered key drivers of tumor recurrence. Further complicating an understanding of GBM, evidence shows that the GSC population is not a pre-ordained and static group of cells but also includes previously differentiated GBM cells that have attained a GSC state secondary to environmental cues. The metabolic behavior of GBM cells undergoing plasticity remains incompletely understood. To that end, we probed the connection between GSCs, environmental cues, and metabolism. Using patient-derived xenograft cells, mouse models, transcriptomics, and metabolic analyses, we found that cell state changes are accompanied by sharp changes in metabolic phenotype. Further, treatment with temozolomide, the current standard of care drug for GBM, altered the metabolism of GBM cells and increased fatty acid uptake both in vitro and in vivo in the plasticity driven GSC population. These results indicate that temozolomide-induced changes in cell state are accompanied by metabolic shifts—a potentially novel target for enhancing the effectiveness of current treatment modalities.
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DOI：
10.4161/cc.8.20.9701
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Heddleston JM;Li Z;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
影响因子：
5.7
作者：
Lee G;Auffinger B;Guo D;Hasan T;Deheeger M;Tobias AL;Kim JY;Atashi F;Zhang L;Lesniak MS;James CD;Ahmed AU
通讯作者：
Ahmed AU
影响因子：
--
作者：
Bayin NS;Frenster JD;Sen R;Si S;Modrek AS;Galifianakis N;Dolgalev I;Ortenzi V;Illa-Bochaca I;Khahera A;Serrano J;Chiriboga L;Zagzag D;Golfinos JG;Doyle W;Tsirigos A;Heguy A;Chesler M;Barcellos-Hoff MH;Snuderl M;Placantonakis DG
通讯作者：
Placantonakis DG
影响因子：
10.5
作者：
Inda, Maria-del-Mar;Bonavia, Rudy;Furnari, Frank
通讯作者：
Furnari, Frank
影响因子：
29
作者：
Marin-Valencia I;Yang C;Mashimo T;Cho S;Baek H;Yang XL;Rajagopalan KN;Maddie M;Vemireddy V;Zhao Z;Cai L;Good L;Tu BP;Hatanpaa KJ;Mickey BE;Matés JM;Pascual JM;Maher EA;Malloy CR;Deberardinis RJ;Bachoo RM
通讯作者：
Bachoo RM