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Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance

Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Sub...

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Autores principales: Iqbal, Mohammad A., Siddiqui, Shumaila, Smith, Kirk, Singh, Prithvi, Kumar, Bhupender, Chouaib, Salem, Chandrasekaran, Sriram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579441/
https://www.ncbi.nlm.nih.gov/pubmed/37854701
http://dx.doi.org/10.1016/j.isci.2023.108059
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author Iqbal, Mohammad A.
Siddiqui, Shumaila
Smith, Kirk
Singh, Prithvi
Kumar, Bhupender
Chouaib, Salem
Chandrasekaran, Sriram
author_facet Iqbal, Mohammad A.
Siddiqui, Shumaila
Smith, Kirk
Singh, Prithvi
Kumar, Bhupender
Chouaib, Salem
Chandrasekaran, Sriram
author_sort Iqbal, Mohammad A.
collection PubMed
description Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Subtype M1 was found to be dependent on bile-acid biosynthesis, whereas M2 showed reliance on methionine pathway, and M3 engaged fatty-acid, nucleotide, and glucose metabolism. The extent of metabolic alterations correlated strongly with tumor aggressiveness and patient outcome. This pattern was reproducible in independent datasets and using in vivo tumor metabolite data. Using machine-learning, we identified robust and generalizable signatures of metabolic subtypes in tumors and cell lines. Experimental inhibition of metabolic pathways in cell lines representing metabolic subtypes revealed subtype-specific sensitivity, therapeutically relevant drugs, and promising combination therapies. Taken together, metabolic stratification of breast cancers can thus aid in predicting patient outcome and designing precision therapies.
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spelling pubmed-105794412023-10-18 Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance Iqbal, Mohammad A. Siddiqui, Shumaila Smith, Kirk Singh, Prithvi Kumar, Bhupender Chouaib, Salem Chandrasekaran, Sriram iScience Article Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Subtype M1 was found to be dependent on bile-acid biosynthesis, whereas M2 showed reliance on methionine pathway, and M3 engaged fatty-acid, nucleotide, and glucose metabolism. The extent of metabolic alterations correlated strongly with tumor aggressiveness and patient outcome. This pattern was reproducible in independent datasets and using in vivo tumor metabolite data. Using machine-learning, we identified robust and generalizable signatures of metabolic subtypes in tumors and cell lines. Experimental inhibition of metabolic pathways in cell lines representing metabolic subtypes revealed subtype-specific sensitivity, therapeutically relevant drugs, and promising combination therapies. Taken together, metabolic stratification of breast cancers can thus aid in predicting patient outcome and designing precision therapies. Elsevier 2023-09-26 /pmc/articles/PMC10579441/ /pubmed/37854701 http://dx.doi.org/10.1016/j.isci.2023.108059 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Iqbal, Mohammad A.
Siddiqui, Shumaila
Smith, Kirk
Singh, Prithvi
Kumar, Bhupender
Chouaib, Salem
Chandrasekaran, Sriram
Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance
title Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance
title_full Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance
title_fullStr Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance
title_full_unstemmed Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance
title_short Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance
title_sort metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579441/
https://www.ncbi.nlm.nih.gov/pubmed/37854701
http://dx.doi.org/10.1016/j.isci.2023.108059
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