Metabolic reprogramming is a common phenomenon in tumorigenesis and tumor progression. Amino acids are important mediators in cancer metabolism, and their kinetics in tumor tissue are far from being understood completely. Mass spectrometry imaging is capable to spatiotemporally trace important endogenous metabolites in biological tissue specimens. In this research, we studied L-[ring-13C6]-labeled phenylalanine and tyrosine kinetics in a human non-small cell lung carcinoma (NSCLC) xenografted mouse model using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI). We investigated the L-[ring-13C6]-Phenylalanine (13C6-Phe) and L-[ring-13C6]-Tyrosine (13C6-Tyr) kinetics at 10 min (n = 4), 30 min (n = 3), and 60 min (n = 4) after tracer injection and sham-treated group (n = 3) at 10 min in mouse-xenograft lung tumor tissues by MALDI-FTICR-MSI. The dynamic changes in the spatial distributions of 19 out of 20 standard amino acids are observed in the tumor tissue. The highest abundance of 13C6-Phe was detected in tumor tissue at 10 min after tracer injection and decreased progressively over time. The overall enrichment of 13C6-Tyr showed a delayed temporal trend compared to 13C6-Phe in tumor caused by the Phe-to-Tyr conversion process. Specifically, 13C6-Phe and 13C6-Tyr showed higher abundances in viable tumor regions compared to non-viable regions. We demonstrated the spatiotemporal intra-tumoral distribution of the essential aromatic amino acid 13C6-Phe and its de-novo synthesized metabolite 13C6-Tyr by MALDI-FTICR-MSI. Our results explore for the first time local phenylalanine metabolism in the context of cancer tissue morphology. This opens a new way to understand amino acid metabolism within the tumor and its microenvironment.

中文翻译：

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L-[环- ¹³ C ₆ ]-标记的苯丙氨酸和酪氨酸动力学在非小细胞肺癌中的质谱成像

代谢重编程是肿瘤发生和肿瘤进展中的常见现象。氨基酸是癌症代谢的重要介质，它们在肿瘤组织中的动力学还远未完全了解。质谱成像能够在时空上追踪生物组织标本中重要的内源性代谢物。在本研究中，我们使用基质辅助激光解吸/电离傅立叶变换离子回旋共振质谱法研究了 L-[环-13C6] 标记的苯丙氨酸和酪氨酸在人类非小细胞肺癌 (NSCLC) 异种移植小鼠模型中的动力学成像（MALDI-FTICR-MSI）。我们研究了 L-[环-13C6]-苯丙氨酸 (13C6-Phe) 和 L-[环-13C6]-酪氨酸 (13C6-Tyr) 在 10 分钟 (n = 4)、30 分钟 (n = 3) 时的动力学，示踪剂注射后 60 分钟 (n = 4) 和假治疗组 (n = 3) 在 10 分钟时通过 MALDI-FTICR-MSI 在小鼠异种移植肺肿瘤组织中进行。在肿瘤组织中观察到 20 种标准氨基酸中 19 种空间分布的动态变化。注射示踪剂后 10 分钟，在肿瘤组织中检测到 13C6-Phe 的最高丰度，并且随着时间的推移逐渐减少。与 13C6-Phe 相比，13C6-Tyr 在肿瘤中的整体富集显示出延迟的时间趋势，这是由 Phe 到 Tyr 转化过程引起的。具体而言，与非活区域相比，13C6-Phe 和 13C6-Tyr 在活肿瘤区域显示出更高的丰度。我们通过 MALDI-FTICR-MSI 证明了必需芳香族氨基酸 13C6-Phe 及其从头合成的代谢物 13C6-Tyr 的肿瘤内时空分布。我们的结果首次在癌组织形态学背景下探索了局部苯丙氨酸代谢。这为了解肿瘤及其微环境中的氨基酸代谢开辟了一条新途径。