# Role of de Novo Synthesis of Sphingolipids in Aneuploid Cells

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $330,813

## Abstract

Abstract
Aneuploidy, a cellular state of having an abnormal number of chromosomes, is a hallmark of cancer. The
degree of aneuploidy significantly correlates with tumor aggressiveness and poor clinical prognosis. Therefore,
studying the cellular processes affected by aneuploidy can improve our understanding of the role of aneuploidy
in tumor biology. Our preliminary results show that de novo synthesis of sphingolipids is increased by
aneuploidy; we therefore propose to identify the molecular mechanisms underlying this effect. Targeting the
synthesis of sphingolipids holds great potential as an anti-cancer strategy that could be used either alone or in
combination with existing therapies. Despite the existence of a large body of literature providing strong
evidence for the misregulation of sphingolipid metabolism in human diseases, including several types of
cancers, the molecular mechanisms that lead to this misregulation are poorly understood. The focus of this
proposal is to unravel the molecular mechanisms that regulate de novo synthesis of sphingolipids and to
decipher how these mechanisms are affected in aneuploid cells. To this end, we propose to: (1) Determine
how aneuploidy increases sphingolipid biosynthesis. Our preliminary data supports the hypothesis that
aneuploid cells rely on the increased activity of serine palmitoyltransferase, the enzyme that controls the first
and irreversible step of sphingolipid synthesis, to proliferate. Therefore, we will investigate the function of
signaling pathways that regulate serine palmitoyltransferase in aneuploidy. In addition, because serine serves
as a precursor for sphingolipids, we will investigate whether aneuploidy leads to increased serine utilization. To
that end, we plan to quantify serine metabolic flux through the sphingolipid pathway in aneuploid cells. Our
studies will provide novel insights into how sphingolipid synthesis is affected in response to aneuploidy. (2)
Determine how sphingolipid levels control the fitness of aneuploid cells. Our preliminary results show that
mutations in four different genes that increase the levels of sphingosine and lower those of ceramide, improve
the fitness of aneuploid cells. Therefore, we will determine, in aneuploid cells, the function of Pkh1/2 kinases
and Cdc55 phosphatase because these signaling molecules are known to act downstream of sphingolipids and
regulate the cell cycle and responses to stress. In addition, we will determine specific cellular pathways and
processes that play an important role in overcoming the detrimental effects of aneuploidy. Gene expression,
proteome content, and phenotypic analyses in combination with genetic approaches will be used to accomplish
this aim. Altogether, our studies will contribute to a better understanding of the physiological role of
sphingolipids in controlling the fitness of aneuploid cells. Determining the mechanisms that control the fitness
of aneuploid cells can be exploited to target aneuploid ca...

## Key facts

- **NIH application ID:** 10084296
- **Project number:** 5R01GM118481-05
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Eduardo Martin Torres
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,813
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084296

## Citation

> US National Institutes of Health, RePORTER application 10084296, Role of de Novo Synthesis of Sphingolipids in Aneuploid Cells (5R01GM118481-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10084296. Licensed CC0.

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