Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

eLife

Tyler Jacks¹  Anna M Westermark²  Sharanya Sivanand³  Matthew G Vander Heiden⁴  David A Tuveson⁵  Shawn M Davidson⁶  Omer Yilmaz⁷  Allison N Lau⁷  Jared R Mayers⁷  Alicia M Darnell⁷  Raphael Ferreira⁷  Christopher R Chin⁷  Zhaoqi Li⁷  Nicholas J Matheson⁷  Evan C Lien⁷  Giulia Biffi⁷  Vasilena Gocheva⁷  Kiera M Sapp⁷  Laura V Danai⁷ 

[1] Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Cambridge, United Kingdom;Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Amherst, United States;Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden;Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States;Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, United States;Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States;Koch Institute for Integrative Cancer Research and the Department of Biology at Massachusetts Institute of Technology, Cambridge, United States;

关键词: pancreatic cancer;    organoid culture;    malic enzyme 1;    PDAC;    pyruvate carboxylase;    metabolic heterogeneity;   

DOI  :  10.7554/eLife.56782

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown