Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer

Abstract Epithelial-to-mesenchymal transition (EMT) is fundamental to both normal tissue development and cancer progression. We hypothesized that EMT plasticity defines a range of metabolic phenotypes and that individual breast epithelial metabolic phenotypes are likely to fall within this phenotypi...

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Autores principales:	Sigurdur Trausti Karvelsson, Qiong Wang, Bylgja Hilmarsdottir, Arnar Sigurdsson, Siver Andreas Moestue, Gunhild Mari Mælandsmo, Skarphedinn Halldorsson, Steinn Gudmundsson, Ottar Rolfsson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/cdfa07e4bd6d4ad0a6994536dab48cac
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spelling	oai:doaj.org-article:cdfa07e4bd6d4ad0a6994536dab48cac2021-12-02T17:23:39ZArgininosuccinate lyase is a metabolic vulnerability in breast development and cancer10.1038/s41540-021-00195-52056-7189https://doaj.org/article/cdfa07e4bd6d4ad0a6994536dab48cac2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41540-021-00195-5https://doaj.org/toc/2056-7189Abstract Epithelial-to-mesenchymal transition (EMT) is fundamental to both normal tissue development and cancer progression. We hypothesized that EMT plasticity defines a range of metabolic phenotypes and that individual breast epithelial metabolic phenotypes are likely to fall within this phenotypic landscape. To determine EMT metabolic phenotypes, the metabolism of EMT was described within genome-scale metabolic models (GSMMs) using either transcriptomic or proteomic data from the breast epithelial EMT cell culture model D492. The ability of the different data types to describe breast epithelial metabolism was assessed using constraint-based modeling which was subsequently verified using 13C isotope tracer analysis. The application of proteomic data to GSMMs provided relatively higher accuracy in flux predictions compared to the transcriptomic data. Furthermore, the proteomic GSMMs predicted altered cholesterol metabolism and increased dependency on argininosuccinate lyase (ASL) following EMT which were confirmed in vitro using drug assays and siRNA knockdown experiments. The successful verification of the proteomic GSMMs afforded iBreast2886, a breast GSMM that encompasses the metabolic plasticity of EMT as defined by the D492 EMT cell culture model. Analysis of breast tumor proteomic data using iBreast2886 identified vulnerabilities within arginine metabolism that allowed prognostic discrimination of breast cancer patients on a subtype-specific level. Taken together, we demonstrate that the metabolic reconstruction iBreast2886 formalizes the metabolism of breast epithelial cell development and can be utilized as a tool for the functional interpretation of high throughput clinical data.Sigurdur Trausti KarvelssonQiong WangBylgja HilmarsdottirArnar SigurdssonSiver Andreas MoestueGunhild Mari MælandsmoSkarphedinn HalldorssonSteinn GudmundssonOttar RolfssonNature PortfolioarticleBiology (General)QH301-705.5ENnpj Systems Biology and Applications, Vol 7, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Sigurdur Trausti Karvelsson Qiong Wang Bylgja Hilmarsdottir Arnar Sigurdsson Siver Andreas Moestue Gunhild Mari Mælandsmo Skarphedinn Halldorsson Steinn Gudmundsson Ottar Rolfsson Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer
description	Abstract Epithelial-to-mesenchymal transition (EMT) is fundamental to both normal tissue development and cancer progression. We hypothesized that EMT plasticity defines a range of metabolic phenotypes and that individual breast epithelial metabolic phenotypes are likely to fall within this phenotypic landscape. To determine EMT metabolic phenotypes, the metabolism of EMT was described within genome-scale metabolic models (GSMMs) using either transcriptomic or proteomic data from the breast epithelial EMT cell culture model D492. The ability of the different data types to describe breast epithelial metabolism was assessed using constraint-based modeling which was subsequently verified using 13C isotope tracer analysis. The application of proteomic data to GSMMs provided relatively higher accuracy in flux predictions compared to the transcriptomic data. Furthermore, the proteomic GSMMs predicted altered cholesterol metabolism and increased dependency on argininosuccinate lyase (ASL) following EMT which were confirmed in vitro using drug assays and siRNA knockdown experiments. The successful verification of the proteomic GSMMs afforded iBreast2886, a breast GSMM that encompasses the metabolic plasticity of EMT as defined by the D492 EMT cell culture model. Analysis of breast tumor proteomic data using iBreast2886 identified vulnerabilities within arginine metabolism that allowed prognostic discrimination of breast cancer patients on a subtype-specific level. Taken together, we demonstrate that the metabolic reconstruction iBreast2886 formalizes the metabolism of breast epithelial cell development and can be utilized as a tool for the functional interpretation of high throughput clinical data.
format	article
author	Sigurdur Trausti Karvelsson Qiong Wang Bylgja Hilmarsdottir Arnar Sigurdsson Siver Andreas Moestue Gunhild Mari Mælandsmo Skarphedinn Halldorsson Steinn Gudmundsson Ottar Rolfsson
author_facet	Sigurdur Trausti Karvelsson Qiong Wang Bylgja Hilmarsdottir Arnar Sigurdsson Siver Andreas Moestue Gunhild Mari Mælandsmo Skarphedinn Halldorsson Steinn Gudmundsson Ottar Rolfsson
author_sort	Sigurdur Trausti Karvelsson
title	Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer
title_short	Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer
title_full	Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer
title_fullStr	Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer
title_full_unstemmed	Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer
title_sort	argininosuccinate lyase is a metabolic vulnerability in breast development and cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cdfa07e4bd6d4ad0a6994536dab48cac
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Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer

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