Sah Samyukta, Ma Xin, Botros Andro, Gaul David A, Yun Sylvia R, Park Eun Young, Kim Olga, Moore Samuel G, Kim Jaeyeon, Fernández Facundo M
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cancers (Basel). 2022 Apr 30;14(9):2262. doi: 10.3390/cancers14092262.
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 ( = 15) and TKO control mice ( = 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.
被诊断为高级别浆液性癌（HGSC）的卵巢癌患者极低的生存率凸显了缺乏有效筛查策略的问题。一个主要障碍是对HGSC在极早期发病机制的了解有限。在此，我们展示了三突变（TKO）HGSC小鼠模型的首个10个月时间分辨血清代谢谱，以及其整个生殖系统的空间脂质组图谱。一种基于高覆盖率液相色谱质谱的代谢组学方法被应用于纵向收集的来自TKO组（n = 15）和TKO对照组小鼠（n = 15）的血清样本，追踪从癌前阶段到肿瘤起始、早期和晚期直至小鼠死亡期间代谢组和脂质组的变化。时间分辨分析显示了17种脂质类别、氨基酸和三羧酸循环代谢物的特定时间趋势，这些与HGSC进展相关。还通过超高分辨率基质辅助激光解吸/电离（MALDI）质谱对生殖系统内的空间脂质分布进行了图谱绘制，并与各种脂质类别的血清脂质谱进行了比较。总之，我们的结果表明脂质和脂肪酸代谢、氨基酸生物合成、三羧酸循环和卵巢类固醇生成的重塑是HGSC发生和发展的关键组成部分。这些代谢改变伴随着能量代谢、线粒体和过氧化物酶体功能、氧化还原稳态和炎症反应的变化，共同支持肿瘤发生。
