Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
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Abstract
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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Funder: Jane Coffin Childs Memorial Fund for Medical Research; FundRef: http://dx.doi.org/10.13039/100001033
Funder: Swedish Foundation for Strategic Research; FundRef: http://dx.doi.org/10.13039/501100001729
Funder: Knut and Alice Wallenberg Foundation; FundRef: http://dx.doi.org/10.13039/501100004063
Funder: Barbro Osher Pro Suecia Foundation; FundRef: http://dx.doi.org/10.13039/100008483
Funder: Howard Hughes Medical Institute; FundRef: http://dx.doi.org/10.13039/100000011
Funder: NIHR Cambridge BRC
Funder: Lustgarten Foundation; FundRef: http://dx.doi.org/10.13039/100005979
Funder: Stand Up To Cancer; FundRef: http://dx.doi.org/10.13039/100009730
Funder: MIT Center for Precision Cancer Medicine
Funder: Ludwig Center at MIT
Funder: Emerald Foundation
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Damon Runyon Cancer Research Foundation (DRG-2367-19)
Damon Runyon Cancer Research Foundation (DRG-2299-17)
National Cancer Institute (K99CA234221)
National Institutes of Health (T32GM007287)
National Cancer Institute (U54CA163109)
Human Frontier Science Program (LT000195/2015-L)
EMBO (ALTF 1203-2014)
MRC (CSF MR/P008801/1)
NHSBT (WPA15-02)
National Institutes of Health (R01CA211184)
National Institutes of Health (R01CA034992)
National Cancer Institute (R01CA168653)
National Cancer Institute (R01CA201276)
National Cancer Institute (R35CA242379)
National Cancer Institute (P30CA14051)