# Reprogramming of creatine metabolism in breast cancer metastasis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $355,850

## Abstract

Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and
metastasize. Several key enzymes have been identified that modulate cancer metabolism. These include
enzymes in glucose, amino acid, nucleic acid, and lipid metabolism, including lactate dehydrogenase A,
glutaminase 1, thymidylate synthase, and choline kinase alpha, to name just a few. Ubiquitous mitochondrial
creatine kinase 1 (CKMT1) is emerging as a novel key enzyme in creatine metabolism of cancer. Few studies
to date have investigated the role of CKMT1 in cancer, and the specific role of CKMT1 in breast cancer
migration, invasion and metastasis remains largely unknown. To close this knowledge gap, we seek to
investigate reprogramming of creatine metabolism in breast cancer. Our preliminary data show that CKMT1
drives cellular creatine (Cr) and phosphocreatine (PCr) concentrations and activates glycolysis in breast
cancer cells. We consistently show in cell lines, mouse models, and patients that creatine metabolite levels
along with CKMT1 expression are downregulated in metastatic breast cancer cells and metastatic tumor
tissues. Overexpression of CKMT1 in metastatic breast cancer cells reduces migration, invasion, and
metastasis, while increasing proliferation and primary tumor growth. Silencing of CKMT1 in nonmetastatic
breast cancer cells increases migration and invasion, which occurs through generation of reactive oxygen
species (ROS) that upregulate adhesion and degradative factors, epithelial-to-mesenchymal transition (EMT),
and signaling pathways. In Aim 1, we will rigorously investigate the cause-and-effect relationships between
reprogramming of creatine metabolism, related molecular pathways, and metastasis-driving cancer cell
properties. In Aim 2, we will assess if genes/enzymes and related molecular pathways responsible for
reprogramming creatine metabolism drive primary tumor growths and metastasis in mouse models of breast
cancer. Our preliminary data show that CKMT1 expression was significantly decreased in clinical breast cancer
metastases as compared to primary breast tumors. In Aim 3, we will further investigate in unique single-patient
tissue microarrays (TMAs) from our rapid autopsy program how creatine metabolic enzyme expression levels
and creatine metabolites, as well as related molecular pathways, are affected when breast cancers
metastasize in patients. In our three Aims, we will test our overall hypothesis that reprogramming of creatine
metabolism participates in driving breast cancer metastasis. Our preliminary findings provide evidence that
creatine metabolism, and in particular CKMT1, holds promise as prognostic indicator and potential therapeutic
target for metastatic breast cancer. Our proposal will significantly advance our understanding of
reprogramming of creatine metabolism in tumor progression and metastasis. We will develop integrated
multiplex matrix-assisted laser desorption/ionization imaging and im...

## Key facts

- **NIH application ID:** 10769870
- **Project number:** 5R01CA264901-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Kristine Glunde
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $355,850
- **Award type:** 5
- **Project period:** 2022-02-08 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769870

## Citation

> US National Institutes of Health, RePORTER application 10769870, Reprogramming of creatine metabolism in breast cancer metastasis (5R01CA264901-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10769870. Licensed CC0.

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