Space- and Time-Resolved Metabolomics of a High-Grade Serous Ovarian Cancer Mouse Model.
Space- and Time-Resolved Metabolomics of a High-Grade Serous Ovarian Cancer Mouse Model.
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作者：
与卵巢癌进展相关的潜在机制在很大程度上仍不清楚，使其成为最致命的癌症之一。为了了解疾病的发病机制，我们的研究涉及对卵巢癌三突变小鼠模型的纵向血清代谢组学分析，该模型捕捉了从疾病开始到小鼠死亡的动态代谢反应。这些实验还补充了三重突变小鼠整个生殖系统的空间脂肪组图谱，使我们能够可视化肿瘤内的组织异质性和脂质变化。提出了与卵巢癌进展相关的代谢改变的综合纵向和空间图，作为了解疾病起源和进展的综合指南。诊断为高级别浆液性癌(HGSC)的卵巢癌患者存活率低得令人沮丧，这突显了缺乏有效的筛查策略。一个主要的障碍是在早期阶段对HGSC发病的潜在机制的了解有限。在这里，我们介绍了第一个10个月的时间分辨的三个突变(TKO)HGSC小鼠模型的血清代谢概况，以及它的整个生殖系统的空间脂体概况。采用基于高效液相色谱-质谱仪的代谢组学方法对TKO(n=15)和TKO对照组(n=15)小鼠的血清样本进行纵向采集，跟踪从癌前阶段到肿瘤起始、早期和晚期直到小鼠死亡的代谢组和脂体的变化。时间分辨分析显示了与HGSC进展相关的17种脂类、氨基酸和TCA循环代谢物的特定时间趋势。还通过超高分辨率基质辅助激光解吸/电离(MALDI)质谱仪绘制了生殖系统内脂类的空间分布图，并与不同脂类的血清脂谱进行了比较。总之，我们的结果表明，脂肪和脂肪酸代谢的重塑、氨基酸的生物合成、TCA循环和卵巢类固醇的生成是HGSC发生和发展的关键组成部分。这些代谢变化伴随着能量代谢、线粒体和过氧化体功能、氧化还原动态平衡和炎症反应的变化，共同支持肿瘤的发生。
The underlying mechanisms associated with ovarian cancer progression remain largely unknown, making it one of the most lethal cancers. To understand the disease pathogenesis, our study involved longitudinal serum metabolomics profiling of a triple-mutant mouse model of ovarian cancer that captured the dynamic metabolic response from disease onset until mouse death. These experiments were complemented with spatial lipidomic profiling of the entire reproductive system of the triple-mutant mice, enabling us to visualize the tissue heterogeneity and lipid alterations within tumors. A combined longitudinal and spatial map of metabolomic alterations associated with ovarian cancer progression is presented, serving as a comprehensive guide towards understanding the disease origin and progression. The dismally low survival rate of ovarian cancer patients diagnosed with high-grade serous carcinoma (HGSC) emphasizes the lack of effective screening strategies. One major obstacle is the limited knowledge of the underlying mechanisms of HGSC pathogenesis at very early stages. Here, we present the first 10-month time-resolved serum metabolic profile of a triple mutant (TKO) HGSC mouse model, along with the spatial lipidome profile of its entire reproductive system. A high-coverage liquid chromatography mass spectrometry-based metabolomics approach was applied to longitudinally collected serum samples from both TKO (n = 15) and TKO control mice (n = 15), tracking metabolome and lipidome changes from premalignant stages to tumor initiation, early stages, and advanced stages until mouse death. Time-resolved analysis showed specific temporal trends for 17 lipid classes, amino acids, and TCA cycle metabolites, associated with HGSC progression. Spatial lipid distributions within the reproductive system were also mapped via ultrahigh-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and compared with serum lipid profiles for various lipid classes. Altogether, our results show that the remodeling of lipid and fatty acid metabolism, amino acid biosynthesis, TCA cycle and ovarian steroidogenesis are critical components of HGSC onset and development. These metabolic alterations are accompanied by changes in energy metabolism, mitochondrial and peroxisomal function, redox homeostasis, and inflammatory response, collectively supporting tumorigenesis.
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通过质谱法对组织中脂质生物化学的MALDI成像。
影响因子：
62.1
作者：
Berry, Karin A. Zemski;Hankin, Joseph A.;Barkley, Robert M.;Spraggins, Jeffrey M.;Caprioli, Richard M.;Murphy, Robert C.
通讯作者：
Murphy, Robert C.
DOI：
10.1073/pnas.2013595117
发表时间：
2020-12-15
影响因子：
11.1
作者：
Kim, Olga;Park, Eun Young;Kim, Jaeyeon
通讯作者：
Kim, Jaeyeon
影响因子：
9.2
作者：
Jimenez-Rojo, Noemi;Leonetti, Manuel D.;Riezman, Howard
通讯作者：
Riezman, Howard
影响因子：
4.6
作者：
Gaul DA;Mezencev R;Long TQ;Jones CM;Benigno BB;Gray A;Fernández FM;McDonald JF
通讯作者：
McDonald JF
影响因子：
3
作者：
Alexandrov T
通讯作者：
Alexandrov T