# Project 2

> **NIH NIH P01** · H. LEE MOFFITT CANCER CTR & RES INST · 2024 · $323,866

## Abstract

PROJECT 2 SUMMARY
INVESTIGATING CYSTEINE ESSENTIALITY IN LUNG CANCER
Cancer cells accumulate significant intracellular cysteine due to increased cystine uptake and loss of
homeostatic control. Cysteine-derived molecules are crucial for cancer cell survival and proliferation as a
consequence of their sulfur moiety, which facilitates diverse functions, including enzyme catalysis, energy
transfer, and redox metabolism. Consistently, we have found that many lung cancer cell lines are highly sensitive
to cystine starvation and lack the capacity for de novo cysteine synthesis, suggesting they are dependent on
exogenous cystine as a source of cysteine. Importantly, the recently developed cyst(e)inase enzyme depletes
extracellular cystine and cysteine efficiently, suggesting it may have therapeutic efficacy against lung cancer.
However, intracellular metabolic circuits can modify the cellular response to starvation independent of
transsulfuration capacity. Thus, understanding the compensatory mechanisms to cysteine starvation is crucial
for efficient therapeutic targeting of cysteine in lung cancer. Importantly, our results suggest the glutathione
synthesis machinery, an important target of the NRF2 transcription factor, has a glutathione-independent role to
protect cells against cysteine starvation-induced ferroptosis. In addition, the tumor microenvironment has
significant levels of alternative sources of cysteine, including glutathione, cystathionine and protein, that are
lacking in cell culture and may promote survival in the absence of cystine. The central hypothesis of this proposal
is that tissue of origin, metabolic responses to cystine starvation, and alteration in sulfur sources within the tumor
microenvironment influence cystine essentiality in lung cancer, thereby leading to targetable metabolic
vulnerabilities. We will test this hypothesis in the following specific aims:
In Aim 1 we will evaluate the influence of tissue and cell of origin on cysteine metabolism and essentiality.
In Aim 2 we will decipher metabolic circuits that dictate responsiveness to cysteine limitation.
In Aim 3 we will evaluate cysteine metabolism in the tumor microenvironment.
The ultimate goal, and the overall impact, of this project is to characterize key determinants of cysteine
metabolism and dependence in lung cancer in order to define opportunities for therapeutic intervention.

## Key facts

- **NIH application ID:** 10898015
- **Project number:** 5P01CA250984-04
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Gina Marie DeNicola
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $323,866
- **Award type:** 5
- **Project period:** 2021-06-25 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898015

## Citation

> US National Institutes of Health, RePORTER application 10898015, Project 2 (5P01CA250984-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10898015. Licensed CC0.

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