Jianhua Cao 1 , Benjamin Balluff 1 , Martijn Arts 2 , Ludwig J. Dubois 3 , Luc J. C. van Loon 4 , Tilman M. Hackeng 5 , Hans M. H. van Eijk 2 , Gert Eijkel 1 , Lara R. Heij 2 , 6 , 7 , Zita Soons 2 , 8 , Steven W. M. Olde Damink 2 , 6 , Ron M. A. Heeren , 1
11 June 2021
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- 13C 6]-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- 13C 6]-Phenylalanine ( 13C 6-Phe) and L-[ring- 13C 6]-Tyrosine ( 13C 6-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 13C 6-Phe was detected in tumor tissue at 10 min after tracer injection and decreased progressively over time. The overall enrichment of 13C 6-Tyr showed a delayed temporal trend compared to 13C 6-Phe in tumor caused by the Phe-to-Tyr conversion process. Specifically, 13C 6-Phe and 13C 6-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 13C 6-Phe and its de-novo synthesized metabolite 13C 6-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.