# The Effect of Serine Source on Nucleotide Metabolism in Cancer: Manipulating Environmental Nutrient Availability to Impact Tumor Growth

> **NIH NIH F31** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $45,520

## Abstract

Project Summary/Abstract
In order to double all biomass components and support cell division, proliferating cancer cells utilize
specialized metabolic programs that affect reliance on particular nutrients. Understanding how the availability
of specific nutrients regulates these biosynthetic networks therefore has great potential for developing cancer
treatment strategies. In particular, production of nucleotides is critical for proliferating cells, and nucleotide
synthesis is the target of many chemotherapies used in the clinic.
To gain insight into the metabolic liabilities of nucleotide production, we assessed how nutrient availability
affects nucleotide levels in cancer cells. Strikingly, we found that availability of extracellular serine is necessary
for the production of nucleotides to support proliferation, even in cancer cells with upregulated intracellular
serine synthesis. Serine can provide carbon substrates for nucleotides, but why the source of serine is
important for nucleotide production is unclear. In considering this question, we noted that serine synthesis has
a high demand for the oxidized cofactor NAD+, whereas direct consumption of serine does not. Indeed,
decreasing NAD+ availability prevents serine synthesis and kills cells in the absence of exogenous serine,
while enhancing NAD+ regeneration restores nucleotide synthesis and proliferation when extracellular serine is
not available. This suggests that cellular redox state can regulate serine synthesis and subsequent use for
nucleotide production. Further, dietary interventions to decrease plasma levels of serine inhibit tumor growth in
mouse models, suggesting that environmental serine availability may create targetable liabilities in cancer.
The overall goal of this project is to determine the role of serine source in regulating nucleotide metabolism to
impact cancer cell proliferation.
To address this question, I propose to:
1) Define how cellular redox state regulates serine synthesis and nucleotide production in tumors
2) Assess how nucleobase salvage compensates for nucleotide synthesis to support proliferation under serine
deprivation
3) Determine how serine availability affects response to chemotherapies that target nucleotide metabolism
By addressing these aims, I will gain insight into how environmental nutrient availability regulates nucleotide
production in proliferating cells. Importantly, this will inform new strategies to target nucleotide metabolism for
cancer therapy. Work on this project will also benefit my training to become a successful independent
researcher. During this time, I will continue to develop in my career by attending and presenting my work at
seminars and conferences, publishing first author papers, and mentoring younger students. Ultimately, work on
this study will train me in addressing the long-term research interests I will pursue in my career: how
fundamental biochemical processes affect the biology of cancer.

## Key facts

- **NIH application ID:** 10003812
- **Project number:** 5F31CA236036-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Frances Flewelling Diehl
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003812

## Citation

> US National Institutes of Health, RePORTER application 10003812, The Effect of Serine Source on Nucleotide Metabolism in Cancer: Manipulating Environmental Nutrient Availability to Impact Tumor Growth (5F31CA236036-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10003812. Licensed CC0.

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