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Metabolic profiles of melanoma patients and PDX models

Rao, Aparna1; Cai, Ling2; Snyman, Marelize2; Walsdorf, Rachel2; Li, Xiangyi2; Wix, Sophia2; Gard, Gabrielle2; Brown, Ariel2; Kim, Juliana2; Santos Patricio, Joao2; Muh, Sarah2; Sandoval, Misty2; Zacharias, Lauren2; Heimdal, Kristen2; Gu, Wen2; Homsi, Jade2; Tillman, Brittny2; Sharma, Rohit2; Vandergriff, Travis2; Solmonson, Ashley2; Faubert, Brandon2; Mathews, Thomas2; Morrison, Sean2; Deberardinis, Ralph2; Gill, Jennifer2

Published Jun 06, 2025 on Dryad. https://doi.org/10.5061/dryad.dncjsxm91

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Abstract

Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumor metabolism in patients has not been closely examined. We developed a parallel workflow to analyze [U-13C]glucose tracing and metabolomics from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labeling, similar to levels in human brain tumors. We observed differences in TCA cycle labelling among PDXs that were similar to differences we observed among the same melanomas in patients, but PDXs had higher labeling in glycolytic intermediates than the same melanomas in patients. We observed consistent metabolic alterations among PDXs and patient tumors that reflected species-specific differences in diet, enzyme expression and other factors. Despite these differences, most of nearly 200 PDXs retained a “metabolic fingerprint” that resembled the same melanomas in patients. PDX metabolism was also largely retained over at least 6 passages. We conclude that awareness of both high- and low-fidelity features will help optimize the use of PDXs to study human cancer metabolism.