Zhang Yang, Guillermier Christelle, De Raedt Thomas, Cox Andrew G, Maertens Ophelia, Yimlamai Dean, Lun Mingyue, Whitney Adam, Maas Richard L, Goessling Wolfram, Cichowski Karen, Steinhauser Matthew L
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
iScience. 2020 Aug 21;23(8):101355. doi: 10.1016/j.isci.2020.101355. Epub 2020 Jul 10.
Malignant tumors exhibit high degrees of genomic heterogeneity at the cellular level, leading to the view that subpopulations of tumor cells drive growth and treatment resistance. To examine the degree to which tumors also exhibit metabolic heterogeneity at the level of individual cells, we employed multi-isotope imaging mass spectrometry (MIMS) to quantify utilization of stable isotopes of glucose and glutamine along with a label for cell division. Mouse models of melanoma and malignant peripheral nerve sheath tumors (MPNSTs) exhibited striking heterogeneity of substrate utilization, evident in both proliferating and non-proliferating cells. We identified a correlation between metabolic heterogeneity, proliferation, and therapeutic resistance. Heterogeneity in metabolic substrate usage as revealed by incorporation of glucose and glutamine tracers is thus a marker for tumor proliferation. Collectively, our data demonstrate that MIMS provides a powerful tool with which to dissect metabolic functions of individual cells within the native tumor environment.
恶性肿瘤在细胞水平上表现出高度的基因组异质性，这导致人们认为肿瘤细胞亚群驱动肿瘤生长和产生治疗抗性。为了研究肿瘤在单个细胞水平上也表现出代谢异质性的程度，我们采用多同位素成像质谱法（MIMS）来量化葡萄糖和谷氨酰胺稳定同位素的利用情况以及细胞分裂标记物。黑色素瘤和恶性外周神经鞘瘤（MPNST）的小鼠模型表现出显著的底物利用异质性，在增殖细胞和非增殖细胞中均很明显。我们发现代谢异质性、增殖和治疗抗性之间存在相关性。因此，通过葡萄糖和谷氨酰胺示踪剂掺入所揭示的代谢底物使用异质性是肿瘤增殖的一个标志物。总体而言，我们的数据表明，MIMS提供了一个强大的工具，可用于剖析天然肿瘤环境中单个细胞的代谢功能。
