Roux Aurelie, Winnard Paul T, Van Voss Marise Heerma, Muller Ludovic, Jackson Shelley N, Hoffer Barry, Woods Amina S, Raman Venu
Structural Biology Unit, Cellular Neurobiology Branch, Integrative Neuroscience NIDA-IRP, NIH, 333 Cassell Drive, Baltimore, MD, 21224, USA.
Division of Cancer Imaging Research, Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Mol Cell Biochem. 2023 Nov;478(11):2567-2580. doi: 10.1007/s11010-023-04685-4. Epub 2023 Mar 8.
Breast cancer brain metastasis (BCBM) has an incidence of 10-30%. It is incurable and the biological mechanisms that promote its progression remain largely undefined. Consequently, to gain insights into BCBM processes, we have developed a spontaneous mouse model of BCBM and in this study found a 20% penetrance of macro-metastatic brain lesion formation. Considering that lipid metabolism is indispensable to metastatic progression, our goal was the mapping of lipid distributions throughout the metastatic regions of the brain. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) of lipids revealed that, relative to surrounding brain tissue, seven long-chain (13-21 carbons long) fatty acylcarnitines, as well as two phosphatidylcholines, two phosphatidylinositols two diacylglycerols, a long-chain phosphatidylethanolamine, and a long-chain sphingomyelin were highly concentrated in the metastatic brain lesion In broad terms, lipids known to be enriched in brain tissues, such as very long-chain (≥ 22 carbons in length) polyunsaturated fatty acid of phosphatidylcholines, phosphatidylethanolamine, sphingomyelins, sulfatides, phosphatidylinositol phosphates, and galactosylceramides, were not found or only found in trace amounts in the metastatic lesion and instead consistently detected in surrounding brain tissues. The data, from this mouse model, highlights an accumulation of fatty acylcarnitines as possible biological makers of a chaotic inefficient vasculature within the metastasis, resulting in relatively inadequate blood flow and disruption of fatty acid β-oxidation due to ischemia/hypoxia.
乳腺癌脑转移（BCBM）的发生率为10%-30%。它无法治愈，促进其进展的生物学机制在很大程度上仍不明确。因此，为了深入了解BCBM过程，我们建立了一种自发的BCBM小鼠模型，并且在本研究中发现大转移脑病变形成的发生率为20%。鉴于脂质代谢对转移进展不可或缺，我们的目标是绘制脂质在整个脑转移区域的分布图。脂质的基质辅助激光解吸/电离质谱成像（MALDI-MSI）显示，相对于周围脑组织，七种长链（13-21个碳原子长）脂肪酰肉碱，以及两种磷脂酰胆碱、两种磷脂酰肌醇、两种二酰基甘油、一种长链磷脂酰乙醇胺和一种长链鞘磷脂在转移性脑病变中高度浓缩。从广义上讲，已知在脑组织中富集的脂质，如磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、硫脂、磷脂酰肌醇磷酸和半乳糖神经酰胺的超长链（≥22个碳原子长）多不饱和脂肪酸，在转移病变中未发现或仅微量发现，而是在周围脑组织中持续检测到。来自该小鼠模型的数据突出了脂肪酰肉碱的积累，这可能是转移灶内血管系统紊乱低效的生物学标志物，导致血流相对不足以及由于缺血/缺氧引起的脂肪酸β氧化中断。
