Creatine riboside is a cancer cell-derived metabolite associated with arginine auxotrophy

Author:

Parker, Amelia L

Toulabi, Leila

Oike, Takahiro

Kanke, Yasuyuki

Patel, Daxeshkumar

Tada, Takeshi

Taylor, Sheryse

Beck, Jessica A

Bowman, Elise

Reyzer, Michelle L

Butcher,Donna

Kuhn, Skyler

Pauly, Gary T

Krausz, Kristopher W

Gonzalez, Frank J

Hussain, S Perwez

Ambs, Stefan

Ryan, Bríd M

Wang, Xin Wei

Harris, Curtis C
Author Address

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA., National Research Resource for Imaging Mass Spectrometry, Vanderbilt University, Nashville, Tennessee, USA., Pathology and Histotechnology Laboratory, Frederick National Laboratory, Frederick, Maryland, USA., Center for Cancer Research Collaborative Bioinformatics Resource., Chemical Biology Laboratory., Laboratory of Metabolism, and., Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.,

Abstract:

The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell-derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.

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Author Address