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Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth. Cell Metab 2016 Nov 08;24(5):685-700

Date

11/10/2016

Pubmed ID

27829138

Pubmed Central ID

PMC7329194

DOI

10.1016/j.cmet.2016.10.011

Scopus ID

2-s2.0-84994680371 (requires institutional sign-in at Scopus site)   281 Citations

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.

Author List

Yang L, Achreja A, Yeung TL, Mangala LS, Jiang D, Han C, Baddour J, Marini JC, Ni J, Nakahara R, Wahlig S, Chiba L, Kim SH, Morse J, Pradeep S, Nagaraja AS, Haemmerle M, Kyunghee N, Derichsweiler M, Plackemeier T, Mercado-Uribe I, Lopez-Berestein G, Moss T, Ram PT, Liu J, Lu X, Mok SC, Sood AK, Nagrath D

Author

Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acids
Animals
Aspartate Aminotransferases
Cancer-Associated Fibroblasts
Carbon
Cell Line, Tumor
Cell Proliferation
Citric Acid Cycle
Disease Models, Animal
Epithelial Cells
Glutamate-Ammonia Ligase
Humans
Metabolome
Mice, Nude
Neoplasms
Nitrogen
Nucleotides
Stromal Cells
Tumor Microenvironment
Up-Regulation