Stable Isotope Tracing Analysis in Cancer Research: Advancements and Challenges in Identifying Dysregulated Cancer Metabolism and Treatment Strategies

Overview

Journal Metabolites

Publisher MDPI

Date 2024 Jun 26

PMID 38921453

Authors

Dalton Hilovsky

Joshua Hartsell

Jamey D Young

Xiaojing Liu

Affiliations

Soon will be listed here.

Abstract

Metabolic reprogramming is a hallmark of cancer, driving the development of therapies targeting cancer metabolism. Stable isotope tracing has emerged as a widely adopted tool for monitoring cancer metabolism both in vitro and in vivo. Advances in instrumentation and the development of new tracers, metabolite databases, and data analysis tools have expanded the scope of cancer metabolism studies across these scales. In this review, we explore the latest advancements in metabolic analysis, spanning from experimental design in stable isotope-labeling metabolomics to sophisticated data analysis techniques. We highlight successful applications in cancer research, particularly focusing on ongoing clinical trials utilizing stable isotope tracing to characterize disease progression, treatment responses, and potential mechanisms of resistance to anticancer therapies. Furthermore, we outline key challenges and discuss potential strategies to address them, aiming to enhance our understanding of the biochemical basis of cancer metabolism.

References

Diaz-Serrano A, Gella P, Jimenez E, Zugazagoitia J, Paz-Ares Rodriguez L . Targeting EGFR in Lung Cancer: Current Standards and Developments. Drugs. 2018; 78(9):893-911. DOI: 10.1007/s40265-018-0916-4. View

Salamanca-Cardona L, Shah H, Poot A, Correa F, Di Gialleonardo V, Lui H . In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors. Cell Metab. 2017; 26(6):830-841.e3. PMC: 5718944. DOI: 10.1016/j.cmet.2017.10.001. View

Nilsson R . Validity of natural isotope abundance correction for metabolic flux analysis. Math Biosci. 2020; 330:108481. DOI: 10.1016/j.mbs.2020.108481. View

Ogrinc N, Kruszewski A, Chaillou P, Saudemont P, Lagadec C, Salzet M . Robot-Assisted SpiderMass for Real-Time Topography Mass Spectrometry Imaging. Anal Chem. 2021; 93(43):14383-14391. DOI: 10.1021/acs.analchem.1c01692. View

Aggarwal R, Vigneron D, Kurhanewicz J . Hyperpolarized 1-[C]-Pyruvate Magnetic Resonance Imaging Detects an Early Metabolic Response to Androgen Ablation Therapy in Prostate Cancer. Eur Urol. 2017; 72(6):1028-1029. PMC: 5723206. DOI: 10.1016/j.eururo.2017.07.022. View

Moiz B, Sriram G, Clyne A . Interpreting metabolic complexity via isotope-assisted metabolic flux analysis. Trends Biochem Sci. 2023; 48(6):553-567. PMC: 10182253. DOI: 10.1016/j.tibs.2023.02.001. View

Wang Z, Ohliger M, Larson P, Gordon J, Bok R, Slater J . Hyperpolarized C MRI: State of the Art and Future Directions. Radiology. 2019; 291(2):273-284. PMC: 6490043. DOI: 10.1148/radiol.2019182391. View

Long C, Antoniewicz M . High-resolution C metabolic flux analysis. Nat Protoc. 2019; 14(10):2856-2877. DOI: 10.1038/s41596-019-0204-0. View

Lewis C, Parker S, Fiske B, McCloskey D, Gui D, Green C . Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell. 2014; 55(2):253-63. PMC: 4106038. DOI: 10.1016/j.molcel.2014.05.008. View

10.

Eskandari R, Kim N, Mamakhanyan A, Saoi M, Zhang G, Berisaj M . Hyperpolarized [5-C,4,4-H,5-N]-L-glutamine provides a means of annotating in vivo metabolic utilization of glutamine. Proc Natl Acad Sci U S A. 2022; 119(19):e2120595119. PMC: 9172133. DOI: 10.1073/pnas.2120595119. View

11.

Hesketh R, Brindle K . Magnetic resonance imaging of cancer metabolism with hyperpolarized C-labeled cell metabolites. Curr Opin Chem Biol. 2018; 45:187-194. DOI: 10.1016/j.cbpa.2018.03.004. View

12.

Vitale I, Shema E, Loi S, Galluzzi L . Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat Med. 2021; 27(2):212-224. DOI: 10.1038/s41591-021-01233-9. View

13.

Planchard D, Janne P, Cheng Y, Yang J, Yanagitani N, Kim S . Osimertinib with or without Chemotherapy in -Mutated Advanced NSCLC. N Engl J Med. 2023; 389(21):1935-1948. DOI: 10.1056/NEJMoa2306434. View

14.

Tsugawa H, cajka T, Kind T, Ma Y, Higgins B, Ikeda K . MS-DIAL: data-independent MS/MS deconvolution for comprehensive metabolome analysis. Nat Methods. 2015; 12(6):523-6. PMC: 4449330. DOI: 10.1038/nmeth.3393. View

15.

Gross M, Demo S, Dennison J, Chen L, Chernov-Rogan T, Goyal B . Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014; 13(4):890-901. DOI: 10.1158/1535-7163.MCT-13-0870. View

16.

Woitek R, Gallagher F . The use of hyperpolarised C-MRI in clinical body imaging to probe cancer metabolism. Br J Cancer. 2021; 124(7):1187-1198. PMC: 8007617. DOI: 10.1038/s41416-020-01224-6. View

17.

Schwaiger-Haber M, Stancliffe E, Anbukumar D, Sells B, Yi J, Cho K . Using mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem. Nat Commun. 2023; 14(1):2876. PMC: 10199024. DOI: 10.1038/s41467-023-38403-x. View

18.

Cai F, Bezwada D, Cai L, Mahar R, Wu Z, Chang M . Comprehensive isotopomer analysis of glutamate and aspartate in small tissue samples. Cell Metab. 2023; 35(10):1830-1843.e5. PMC: 10732579. DOI: 10.1016/j.cmet.2023.07.013. View

19.

Liu R, Li J, Lan Y, Nguyen T, Chen Y, Yang Z . Quantifying Cell Heterogeneity and Subpopulations Using Single Cell Metabolomics. Anal Chem. 2023; 95(18):7127-7133. PMC: 11476832. DOI: 10.1021/acs.analchem.2c05245. View

20.

Fendt S, Frezza C, Erez A . Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy. Cancer Discov. 2020; 10(12):1797-1807. PMC: 7710573. DOI: 10.1158/2159-8290.CD-20-0844. View