Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth = 종양 미세환경을 조절하는 종양의 생장에서 글루타민 합성의 표적화

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Title
Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth = 종양 미세환경을 조절하는 종양의 생장에서 글루타민 합성의 표적화
Author(s)
L Yang; A Achreja; T L Yeung; L S Mangala; D Jiang; C Han; J Baddour; J C Marini; J Ni; R Nakahara; S Wahlig; L Chiba; S H Kim; J Morse; S Pradeep; A S Nagaraja; M Haemmerle; Kyung Hee Noh; M Derichsweiler; T Plackemeier; I Mercado-Uribe; G Lopez-Berestein; T Moss; P T Ram; J Liu; X Lu; S C Mok; A K Sood; D Nagrath
Bibliographic Citation
Cell Metabolism, vol. 24, no. 5, pp. 685-700
Publication Year
2016
Abstract
Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make cancer cells vulnerable has remained challenging and elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through an upregulated glutamine anabolic pathway. This dysfunctional stromal metabolism confers atypical metabolic flexibility and adaptive mechanisms in stromal cells, allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in TME. Using an orthotopic mouse model for ovarian carcinoma, we find that co-targeting glutamine synthetase in stroma and glutaminase in?cancer cells reduces tumor weight, nodules, and metastasis. We present a synthetic lethal approach to target tumor stroma and cancer cells simultaneously for desirable therapeutic outcomes
ISSN
1550-4131
Publisher
Elsevier-Cell Press
DOI
http://dx.doi.org/10.1016/j.cmet.2016.10.011
Type
Article
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
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