Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

Allison N. Lau; Zhaoqi Li; Laura V. Danai; Anna M. Westermark; Alicia M. Darnell; Raphael Ferreira; Vasilena Gocheva; Sharanya Sivanand; Evan C. Lien; Kiera M. Sapp; Jared R. Mayers; Giulia Biffi; Christopher R. Chin; Shawn M. Davidson; David A. Tuveson; Tyler Jacks; Nicholas J. Matheson; Omer Yilmaz; Matthew G. Vander Heiden

doi:10.7554/eLife.56782

Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
Journal article, 2020

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.

metabolic heterogeneity

organoid culture

PDAC

malic enzyme 1

cancer biology

pyruvate carboxylase

pancreatic cancer

mouse

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