TY - JOUR
T1 - Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth
AU - Yang, Lifeng
AU - Achreja, Abhinav
AU - Yeung, Tsz Lun
AU - Mangala, Lingegowda S.
AU - Jiang, Dahai
AU - Han, Cecil
AU - Baddour, Joelle
AU - Marini, Juan C.
AU - Ni, Joseph
AU - Nakahara, Ryuichi
AU - Wahlig, Stephen
AU - Chiba, Lisa
AU - Kim, Sun Hye
AU - Morse, Joshua
AU - Pradeep, Sunila
AU - Nagaraja, Archana Sidalaghatta
AU - Haemmerle, Monika
AU - Kyunghee, Noh
AU - Derichsweiler, Mathew
AU - Plackemeier, Thomas
AU - Mercado-Uribe, Imelda
AU - Lopez-Berestein, Gabriel
AU - Moss, Tyler
AU - Ram, Prahlad T.
AU - Liu, Jinsong
AU - Lu, Xiongbin
AU - Mok, Samuel C.
AU - Sood, Anil K.
AU - Nagrath, Deepak
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/11/8
Y1 - 2016/11/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2016.10.011
DO - 10.1016/j.cmet.2016.10.011
M3 - Article
C2 - 27829138
AN - SCOPUS:84994680371
SN - 1550-4131
VL - 24
SP - 685
EP - 700
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -