Metabolic memory underlying minimal residual disease in breast cancer

Abstract Tumor relapse from treatment‐resistant cells (minimal residual disease, MRD) underlies most breast cancer‐related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi‐omics data from a tractable organoid system with a...

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Autores principales:	Ksenija Radic Shechter, Eleni Kafkia, Katharina Zirngibl, Sylwia Gawrzak, Ashna Alladin, Daniel Machado, Christian Lüchtenborg, Daniel C Sévin, Britta Brügger, Kiran R Patil, Martin Jechlinger
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	glycolysis metabolic modeling multi‐omics integration oncogenic memory organoids Biology (General) QH301-705.5 Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/c0276c0d71bf4b688df33f54bc4ee1f4
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spelling	oai:doaj.org-article:c0276c0d71bf4b688df33f54bc4ee1f42021-11-11T11:30:47ZMetabolic memory underlying minimal residual disease in breast cancer1744-429210.15252/msb.202010141https://doaj.org/article/c0276c0d71bf4b688df33f54bc4ee1f42021-10-01T00:00:00Zhttps://doi.org/10.15252/msb.202010141https://doaj.org/toc/1744-4292Abstract Tumor relapse from treatment‐resistant cells (minimal residual disease, MRD) underlies most breast cancer‐related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi‐omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non‐proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo‐adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment‐resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small‐molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post‐treatment care to prevent breast tumor recurrence.Ksenija Radic ShechterEleni KafkiaKatharina ZirngiblSylwia GawrzakAshna AlladinDaniel MachadoChristian LüchtenborgDaniel C SévinBritta BrüggerKiran R PatilMartin JechlingerWileyarticleglycolysismetabolic modelingmulti‐omics integrationoncogenic memoryorganoidsBiology (General)QH301-705.5Medicine (General)R5-920ENMolecular Systems Biology, Vol 17, Iss 10, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glycolysis metabolic modeling multi‐omics integration oncogenic memory organoids Biology (General) QH301-705.5 Medicine (General) R5-920
spellingShingle	glycolysis metabolic modeling multi‐omics integration oncogenic memory organoids Biology (General) QH301-705.5 Medicine (General) R5-920 Ksenija Radic Shechter Eleni Kafkia Katharina Zirngibl Sylwia Gawrzak Ashna Alladin Daniel Machado Christian Lüchtenborg Daniel C Sévin Britta Brügger Kiran R Patil Martin Jechlinger Metabolic memory underlying minimal residual disease in breast cancer
description	Abstract Tumor relapse from treatment‐resistant cells (minimal residual disease, MRD) underlies most breast cancer‐related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi‐omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non‐proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo‐adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment‐resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small‐molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post‐treatment care to prevent breast tumor recurrence.
format	article
author	Ksenija Radic Shechter Eleni Kafkia Katharina Zirngibl Sylwia Gawrzak Ashna Alladin Daniel Machado Christian Lüchtenborg Daniel C Sévin Britta Brügger Kiran R Patil Martin Jechlinger
author_facet	Ksenija Radic Shechter Eleni Kafkia Katharina Zirngibl Sylwia Gawrzak Ashna Alladin Daniel Machado Christian Lüchtenborg Daniel C Sévin Britta Brügger Kiran R Patil Martin Jechlinger
author_sort	Ksenija Radic Shechter
title	Metabolic memory underlying minimal residual disease in breast cancer
title_short	Metabolic memory underlying minimal residual disease in breast cancer
title_full	Metabolic memory underlying minimal residual disease in breast cancer
title_fullStr	Metabolic memory underlying minimal residual disease in breast cancer
title_full_unstemmed	Metabolic memory underlying minimal residual disease in breast cancer
title_sort	metabolic memory underlying minimal residual disease in breast cancer
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/c0276c0d71bf4b688df33f54bc4ee1f4
work_keys_str_mv	AT ksenijaradicshechter metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT elenikafkia metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT katharinazirngibl metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT sylwiagawrzak metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT ashnaalladin metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT danielmachado metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT christianluchtenborg metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT danielcsevin metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT brittabrugger metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT kiranrpatil metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer AT martinjechlinger metabolicmemoryunderlyingminimalresidualdiseaseinbreastcancer
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Metabolic memory underlying minimal residual disease in breast cancer

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