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. 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.

Li, ZhaoqiMassachusetts Institute of Technology (MIT) (author)
Danai, Laura V.University of Massachusetts,Massachusetts Institute of Technology (MIT) (author)
Westermark, Anna M.Massachusetts Institute of Technology (MIT) (author)
Darnell, Alicia M.Massachusetts Institute of Technology (MIT) (author)
Ferreira, Raphael,1990Massachusetts Institute of Technology (MIT),Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)rapfer (author)
Gocheva, VasilenaMassachusetts Institute of Technology (MIT) (author)
Sivanand, SharanyaMassachusetts Institute of Technology (MIT) (author)
Lien, Evan C.Massachusetts Institute of Technology (MIT) (author)
Sapp, Kiera M.Massachusetts Institute of Technology (MIT) (author)
Mayers, Jared R.Massachusetts Institute of Technology (MIT) (author)
Biffi, GiuliaUniversity Of Cambridge (author)
Chin, Christopher R.Massachusetts Institute of Technology (MIT) (author)
Davidson, Shawn M.Princeton University,Massachusetts Institute of Technology (MIT) (author)
Tuveson, David A. (author)
Jacks, TylerMassachusetts Institute of Technology (MIT) (author)
Matheson, Nicholas J.Massachusetts Institute of Technology (MIT),University Of Cambridge (author)
Yilmaz, OmerMassachusetts General Hospital,Massachusetts Institute of Technology (MIT) (author)
Vander Heiden, Matthew G.Massachusetts Institute of Technology (MIT),Dana-Farber Cancer Institute (author)
Massachusetts Institute of Technology (MIT)University of Massachusetts (creator_code:org_t)

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