# Non-essential amino acids and sphingolipid diversity in cancer progression

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $364,668

## Abstract

Abstract
Cancer cells reprogram metabolic pathways to survive and proliferate in response to changes in their
microenvironment. While oncogenic pathways sustain glycolytic metabolism to enhance survival during
tumorigenesis, mitochondrial metabolism is significantly altered upon loss of extracellular matrix (ECM) contact
and growth under anchorage-independent conditions. By applying metabolic flux analysis (MFA) to tumor
spheroids, we have identified particular changes in serine, alanine, and sphingolipid metabolism that control
tumor cell growth in such microenvironments. Many tumors amplify or overexpress phosphohydroxypyruvate
dehydrogenase (PHGDH) and other enzymes within the serine synthesis pathway to support growth, though the
specific mechanisms through which this pathway supports aggressive tumor growth remain unclear. Serine and
alanine metabolism are linked via sphingolipid biosynthesis, where the enzyme serine palmitoyltransferase
(SPT) produces toxic deoxysphingolipids (doxSLs) in the context of abundant alanine and low serine levels.
These atypical doxSLs are produced at higher rates during anchorage-independent growth and compromise
mitochondrial metabolism to mitigate spheroid growth. By modulating the production and availability of serine,
alanine, and sphingolipids we can control in vitro and in vivo tumor growth. These findings provide a novel and
unexplored mechanism through which serine deprivation limits cancer cell growth. This proposal aims to exploit
the production of doxSLs in tumors by manipulating dietary amino acids and endogenous serine synthesis to
mitigate tumor growth and metastasis. In Aim 1 we will apply MFA to characterize changes in mitochondrial and
amino acid pathways during anchorage-independent growth. In Aim 2 we will quantify how sphingolipid
biosynthesis is impacted during spheroid growth and determine why doxSL species are toxic to tumor cells. In
Aim 3 we will design specifically formulated diets that mitigate tumor growth and metastasis by modulating doxSL
production when administered alone or in combination with PHGDH inhibitors. We will also engineer the
sphingolipid biosynthesis pathway in tumor cells to validate our central hypothesis. If successful, this proposal
will define a novel mechanism through which serine deprivation limits tumor growth that can be exploited via
dietary interventions and used to identify responsive tumor types in the clinic.

## Key facts

- **NIH application ID:** 9928906
- **Project number:** 5R01CA234245-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christian Michael Metallo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,668
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928906

## Citation

> US National Institutes of Health, RePORTER application 9928906, Non-essential amino acids and sphingolipid diversity in cancer progression (5R01CA234245-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928906. Licensed CC0.

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