School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China.
Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China.
Theranostics. 2020 May 30;10(16):7070-7082. doi: 10.7150/thno.45543. eCollection 2020.
New insights into tumor-associated metabolic reprogramming have provided novel vulnerabilities that can be targeted for cancer therapy. Here, we propose a mass spectrometry imaging (MSI)-based metabolomic strategy to visualize the spatially resolved reprogramming of carnitine metabolism in heterogeneous breast cancer. A wide carnitine coverage MSI method was developed to investigate the spatial alternations of carnitines in cancer tissues of xenograft mouse models and human samples. Spatial expression of key metabolic enzymes that are closely associated with the altered carnitines was examined in adjacent cancer tissue sections. A total of 17 carnitines, including L-carnitine, 6 short-chain acylcarnitines, 3 middle-chain acylcarnitines, and 7 long-chain acylcarnitines were imaged. L-carnitine and short-chain acylcarnitines are significantly reprogrammed in breast cancer. A classification model based on the carnitine profiles of 170 cancer samples and 128 normal samples enables an accurate identification of breast cancer. CPT 1A, CPT 2, and CRAT, which are extensively involved in carnitine system-mediated fatty acid β-oxidation pathway were also found to be abnormally expressed in breast cancer. Remarkably, the expressions of CPT 2 and CRAT were found for the first time to be altered in breast cancer. These data not only expand our understanding of the complex tumor metabolic reprogramming, but also provide the first evidence that carnitine metabolism is reprogrammed at both the metabolite and enzyme levels in breast cancer.
肿瘤相关代谢重编程的新见解为癌症治疗提供了新的靶点。在这里，我们提出了一种基于质谱成像（MSI）的代谢组学策略，用于可视化异质性乳腺癌中肉碱代谢的空间重编程。开发了一种广泛的肉碱覆盖 MSI 方法，以研究异种移植小鼠模型和人类样本中癌症组织中肉碱的空间变化。在相邻的癌症组织切片中检查了与改变的肉碱密切相关的关键代谢酶的空间表达。共成像了 17 种肉碱，包括 L-肉碱、6 种短链酰基辅酶 A、3 种中链酰基辅酶 A 和 7 种长链酰基辅酶 A。L-肉碱和短链酰基辅酶 A 在乳腺癌中显著重编程。基于 170 个癌症样本和 128 个正常样本的肉碱谱的分类模型能够准确识别乳腺癌。广泛参与肉碱系统介导的脂肪酸β-氧化途径的 CPT 1A、CPT 2 和 CRAT 也被发现异常表达在乳腺癌中。值得注意的是，CPT 2 和 CRAT 的表达首次被发现发生改变。这些数据不仅扩展了我们对复杂肿瘤代谢重编程的理解，而且还提供了第一个证据，表明肉碱代谢在乳腺癌中在代谢物和酶水平上都被重新编程。
