Generation of 2,000 breast cancer metabolic landscapes reveals a poor prognosis group with active serotonin production

Scientific Reports
Vytautas LeoncikasNick J Plant

Abstract

A major roadblock in the effective treatment of cancers is their heterogeneity, whereby multiple molecular landscapes are classified as a single disease. To explore the contribution of cellular metabolism to cancer heterogeneity, we analyse the Metabric dataset, a landmark genomic and transcriptomic study of 2,000 individual breast tumours, in the context of the human genome-scale metabolic network. We create personalized metabolic landscapes for each tumour by exploring sets of active reactions that satisfy constraints derived from human biochemistry and maximize congruency with the Metabric transcriptome data. Classification of the personalized landscapes derived from 997 tumour samples within the Metabric discovery dataset reveals a novel poor prognosis cluster, reproducible in the 995-sample validation dataset. We experimentally follow mechanistic hypotheses resulting from the computational study and establish that active serotonin production is a major metabolic feature of the poor prognosis group. These data support the reconsideration of concomitant serotonin-specific uptake inhibitors treatment during breast cancer chemotherapy.

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Citations

Oct 29, 2017·Proceedings of the National Academy of Sciences of the United States of America·Jae Yong RyuSang Yup Lee
Jul 21, 2017·NPJ Systems Biology and Applications·Huihai WuAndrzej M Kierzek
Aug 17, 2019·Frontiers in Immunology·Ana Luisa Palacios-AcedoLaurence Panicot-Dubois
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Aug 28, 2020·BMC Complementary Medicine and Therapies·Shuangshuang MaZhiyong Yu
Oct 21, 2019·Pharmacology & Therapeutics·Michael Bader
May 1, 2021·International Journal of Molecular Sciences·Kenneth K Wu
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·William D GwynneJohn A Hassell
Jul 10, 2021·Molecular and Cellular Endocrinology·Yurong Zheng, Antoine E Karnoub
Oct 24, 2017·ACS Medicinal Chemistry Letters·Jiney JoseKevin N Dalby
Aug 25, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Di YeFeng Bi

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Methods Mentioned

BETA
ELISA

Software Mentioned

package
JyMet
SurreyFBA
DAVID
Illumina
GraphPad
Metabric
R
R Bioconductor
iMAT

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