# Reducing serine biosynthesis and utilization as a novel approach for colon cancer prevention

> **NIH NIH K22** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $229,478

## Abstract

ABSTRACT
 My ongoing work has focused on investigating the role of gut luminal and host metabolites in
gastrointestinal neoplasia with a focus on prevention. One such study using the azoxymethane-induced mouse
colon tumor model, demonstrated that targeted metabolite profiling of feces can non-invasively inform on the
presence of colon adenomas. Metabolomic analysis of tumor tissue also revealed aberrant metabolism
including increased serine biosynthesis. Other work has focused on the interplay between luminal and host
metabolism using the APCMin/+ mouse model of intestinal tumorigenesis. In this study, I demonstrated that
administration of the chemopreventive agent celecoxib shifted the gut luminal microbiota and metabolome in
association with reducing intestinal stem cell proliferation and polyp burden. These findings indicate an
important interplay between luminal changes and the host epithelium. In light of these findings I have been
carrying out a study focused on the role of the non-essential amino acid serine in colon neoplasia. This work
demonstrates that status of the tumor suppressor gene APC, loss of which is an early event in colorectal
cancer (CRC) development, controls serine biosynthesis and downstream one-carbon metabolism. Moreover, I
showed that the serine biosynthetic enzyme PSAT1 is elevated in multiple stages of human colon neoplasia
and its high expression is correlated with poor outcome in CRC. Importantly, I've shown that deletion of PSAT1
reduces CRC cell proliferation, an effect that is accentuated by removal of exogenous serine.
 The studies that will be executed as part of this K22 award are a natural extension of the work
described above and will directly test whether serine supports colon tumor development and growth. To test
this I will utilize a novel mouse model in which PSAT1 can be knocked down. Mechanistic in vitro work will be
carried out using intestinal organoids and cell culture systems to evaluate how serine utilization supports
neoplastic cell proliferation. Lastly, in light of the known metabolic plasticity of neoplastic cells, I will determine
whether targeting both endogenous and exogenous serine synergistically reduces colon tumor burden. Taken
together, this work has the potential to reveal a novel pathway important for CRC. Beyond the scope of this
award, studies will be carried out to evaluate whether this pathway is a viable target for CRC treatment and
potentially other cancers. Importantly, this award will be key for enabling me to establish an independent
career in cancer research.

## Key facts

- **NIH application ID:** 9858309
- **Project number:** 5K22CA226033-02
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** David C Montrose
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $229,478
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858309

## Citation

> US National Institutes of Health, RePORTER application 9858309, Reducing serine biosynthesis and utilization as a novel approach for colon cancer prevention (5K22CA226033-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858309. Licensed CC0.

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