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Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. T...

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Autores principales: Lau, Allison N, Li, Zhaoqi, Danai, Laura V, Westermark, Anna M, Darnell, Alicia M, Ferreira, Raphael, Gocheva, Vasilena, Sivanand, Sharanya, Lien, Evan C, Sapp, Kiera M, Mayers, Jared R, Biffi, Giulia, Chin, Christopher R, Davidson, Shawn M, Tuveson, David A, Jacks, Tyler, Matheson, Nicholas J, Yilmaz, Omer, Vander Heiden, Matthew G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406355/
https://www.ncbi.nlm.nih.gov/pubmed/32648540
http://dx.doi.org/10.7554/eLife.56782
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author Lau, Allison N
Li, Zhaoqi
Danai, Laura V
Westermark, Anna M
Darnell, Alicia M
Ferreira, Raphael
Gocheva, Vasilena
Sivanand, Sharanya
Lien, Evan C
Sapp, Kiera M
Mayers, Jared R
Biffi, Giulia
Chin, Christopher R
Davidson, Shawn M
Tuveson, David A
Jacks, Tyler
Matheson, Nicholas J
Yilmaz, Omer
Vander Heiden, Matthew G
author_facet Lau, Allison N
Li, Zhaoqi
Danai, Laura V
Westermark, Anna M
Darnell, Alicia M
Ferreira, Raphael
Gocheva, Vasilena
Sivanand, Sharanya
Lien, Evan C
Sapp, Kiera M
Mayers, Jared R
Biffi, Giulia
Chin, Christopher R
Davidson, Shawn M
Tuveson, David A
Jacks, Tyler
Matheson, Nicholas J
Yilmaz, Omer
Vander Heiden, Matthew G
author_sort Lau, Allison N
collection PubMed
description Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.
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spelling pubmed-74063552020-08-06 Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma Lau, Allison N Li, Zhaoqi Danai, Laura V Westermark, Anna M Darnell, Alicia M Ferreira, Raphael Gocheva, Vasilena Sivanand, Sharanya Lien, Evan C Sapp, Kiera M Mayers, Jared R Biffi, Giulia Chin, Christopher R Davidson, Shawn M Tuveson, David A Jacks, Tyler Matheson, Nicholas J Yilmaz, Omer Vander Heiden, Matthew G eLife Cancer Biology Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue. eLife Sciences Publications, Ltd 2020-07-10 /pmc/articles/PMC7406355/ /pubmed/32648540 http://dx.doi.org/10.7554/eLife.56782 Text en © 2020, Lau et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Lau, Allison N
Li, Zhaoqi
Danai, Laura V
Westermark, Anna M
Darnell, Alicia M
Ferreira, Raphael
Gocheva, Vasilena
Sivanand, Sharanya
Lien, Evan C
Sapp, Kiera M
Mayers, Jared R
Biffi, Giulia
Chin, Christopher R
Davidson, Shawn M
Tuveson, David A
Jacks, Tyler
Matheson, Nicholas J
Yilmaz, Omer
Vander Heiden, Matthew G
Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
title Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
title_full Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
title_fullStr Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
title_full_unstemmed Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
title_short Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
title_sort dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406355/
https://www.ncbi.nlm.nih.gov/pubmed/32648540
http://dx.doi.org/10.7554/eLife.56782
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