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Mol Syst Biol. 2017 Dec 1;13(12):956. doi: 10.15252/msb.20177739.

An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer.

Author information

1
Department of Computer Science, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, USA noamaus@gmail.com andrew.freywald@usask.ca franco.vizeacoumar@usask.ca eyruppin@gmail.com.
2
Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
3
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
4
Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel.
5
Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada noamaus@gmail.com andrew.freywald@usask.ca franco.vizeacoumar@usask.ca eyruppin@gmail.com.
6
Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, Canada.

Abstract

Metabolic alterations play an important role in cancer and yet, few metabolic cancer driver genes are known. Here we perform a combined genomic and metabolic modeling analysis searching for metabolic drivers of colorectal cancer. Our analysis predicts FUT9, which catalyzes the biosynthesis of Ley glycolipids, as a driver of advanced-stage colon cancer. Experimental testing reveals FUT9's complex dual role; while its knockdown enhances proliferation and migration in monolayers, it suppresses colon cancer cells expansion in tumorspheres and inhibits tumor development in a mouse xenograft models. These results suggest that FUT9's inhibition may attenuate tumor-initiating cells (TICs) that are known to dominate tumorspheres and early tumor growth, but promote bulk tumor cells. In agreement, we find that FUT9 silencing decreases the expression of the colorectal cancer TIC marker CD44 and the level of the OCT4 transcription factor, which is known to support cancer stemness. Beyond its current application, this work presents a novel genomic and metabolic modeling computational approach that can facilitate the systematic discovery of metabolic driver genes in other types of cancer.

KEYWORDS:

FUT9; colon cancer; genome‐scale metabolic modeling; oncogene; tumor suppressor

PMID:
29196508
PMCID:
PMC5740504

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