Cysteine Acquisition and Utilization in Lung Adenocarcinoma

Cysteine-derived molecules are crucial for cancer cell survival and proliferation because of their sulfur moiety, which facilitates diverse functions, including enzyme catalysis, energy transfer, and redox metabolism. This project aims to challenge the current paradigm that tumor cells primarily obtain cysteine through xCT-mediated cystine import. Our preliminary data reveal that the tumor microenvironment is highly reduced, with cysteine available predominantly in its reduced form and millimolar concentrations of glutathione (GSH) that maintain cysteine in this state. This proposal will investigate three critical aspects of tumor cysteine metabolism: (1) the origins and mechanisms regulating cysteine availability in the tumor microenvironment, with focus on GSH- mediated copper chelation and cystine reduction; (2) the identification and characterization of cysteine transporters and their context-dependent requirements across different tumor regions; and (3) how the availability of reduced cysteine versus oxidized cystine fundamentally reprograms cellular metabolism by bypassing xCT-mediated cystine import, thereby preserving cellular NADPH and glutamate pools. We will leverage innovative approaches including quantitative metabolomics with optimized derivatization methods, in vivo stable isotope tracing, MALDI imaging mass spectrometry, and specialized culture systems that recapitulate the unique metabolite composition of the tumor microenvironment. Understanding how the reducing tumor microenvironment influences cysteine availability and utilization is highly relevant to cancer research, as it reveals the true metabolic dependencies of cancer cells in their native context. This work will identify novel therapeutic targets that better reflect in vivo tumor metabolism, potentially leading to more effective treatments for lung adenocarcinoma and other cancers where cysteine metabolism is dysregulated. Project Number: 1R01CA309659-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Gina DeNicola | Institution: H. LEE MOFFITT CANCER CTR & RES INST, TAMPA, FL | Award Amount: $687,593 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 BTC-Y (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11305646