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Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function

The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particular...

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Autores principales: Bennett, Neal K., Nakaoka, Hiroki J., Laurent, Danny, Okimoto, Ross A., Sei, Yoshitaka, Horvai, Andrew E., Bivona, Trever G., ten Hoeve, Johanna, Graeber, Thomas G., Nakamura, Ken, Nakamura, Jean L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498964/
https://www.ncbi.nlm.nih.gov/pubmed/36137002
http://dx.doi.org/10.1371/journal.pbio.3001753
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author Bennett, Neal K.
Nakaoka, Hiroki J.
Laurent, Danny
Okimoto, Ross A.
Sei, Yoshitaka
Horvai, Andrew E.
Bivona, Trever G.
ten Hoeve, Johanna
Graeber, Thomas G.
Nakamura, Ken
Nakamura, Jean L.
author_facet Bennett, Neal K.
Nakaoka, Hiroki J.
Laurent, Danny
Okimoto, Ross A.
Sei, Yoshitaka
Horvai, Andrew E.
Bivona, Trever G.
ten Hoeve, Johanna
Graeber, Thomas G.
Nakamura, Ken
Nakamura, Jean L.
author_sort Bennett, Neal K.
collection PubMed
description The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines, we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells down-regulate glycolytic mechanisms. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors.
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spelling pubmed-94989642022-09-23 Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function Bennett, Neal K. Nakaoka, Hiroki J. Laurent, Danny Okimoto, Ross A. Sei, Yoshitaka Horvai, Andrew E. Bivona, Trever G. ten Hoeve, Johanna Graeber, Thomas G. Nakamura, Ken Nakamura, Jean L. PLoS Biol Discovery Report The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines, we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells down-regulate glycolytic mechanisms. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors. Public Library of Science 2022-09-22 /pmc/articles/PMC9498964/ /pubmed/36137002 http://dx.doi.org/10.1371/journal.pbio.3001753 Text en © 2022 Bennett et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Discovery Report
Bennett, Neal K.
Nakaoka, Hiroki J.
Laurent, Danny
Okimoto, Ross A.
Sei, Yoshitaka
Horvai, Andrew E.
Bivona, Trever G.
ten Hoeve, Johanna
Graeber, Thomas G.
Nakamura, Ken
Nakamura, Jean L.
Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
title Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
title_full Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
title_fullStr Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
title_full_unstemmed Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
title_short Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
title_sort primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
topic Discovery Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498964/
https://www.ncbi.nlm.nih.gov/pubmed/36137002
http://dx.doi.org/10.1371/journal.pbio.3001753
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