Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth.
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.
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Lifeng
L
Yang
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Abhinav
A
Achreja
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA.
Tsz-Lun
TL
Yeung
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, MD Anderson, Houston, TX 77030, USA.
Lingegowda S
LS
Mangala
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, MD Anderson, Houston, TX 77030, USA.
Dahai
D
Jiang
Department of Cancer Biology, University of Texas, MD Anderson, Houston, TX 77030, USA.
Cecil
C
Han
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Joelle
J
Baddour
Baylor College of Medicine, Houston, TX 77005, USA.
Juan C
JC
Marini
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Joseph
J
Ni
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Ryuichi
R
Nakahara
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Bioengineering, Rice University, Houston, TX 77005, USA.
Stephen
S
Wahlig
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Lisa
L
Chiba
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Sun Hye
SH
Kim
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA.
Joshua
J
Morse
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, MD Anderson, Houston, TX 77030, USA.
Sunila
S
Pradeep
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, MD Anderson, Houston, TX 77030, USA.
Archana Sidalaghatta
AS
Nagaraja
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, MD Anderson, Houston, TX 77030, USA.
Monika
M
Haemmerle
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, MD Anderson, Houston, TX 77030, USA; Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
Noh
N
Kyunghee
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Mathew
M
Derichsweiler
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
Thomas
T
Plackemeier
Department of Pathology, University of Texas, MD Anderson, Houston, TX 77030, USA.
Imelda
I
Mercado-Uribe
Center for RNA Interference and Non-Coding RNA, University of Texas, MD Anderson, Houston, TX 77030, USA.
Gabriel
G
Lopez-Berestein
Department of Systems Biology, University of Texas, MD Anderson, Houston, TX 77030, USA.
Tyler
T
Moss
Department of Systems Biology, University of Texas, MD Anderson, Houston, TX 77030, USA.
Prahlad T
PT
Ram
Department of Pathology, University of Texas, MD Anderson, Houston, TX 77030, USA.
Jinsong
J
Liu
Department of Cancer Biology, University of Texas, MD Anderson, Houston, TX 77030, USA.
Xiongbin
X
Lu
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA.
Samuel C
SC
Mok
Department of Gynecological Oncology and Reproductive Medicine, University of Texas, MD Anderson, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas, MD Anderson, Houston, TX 77030, USA. Electronic address: asood@mdanderson.org.
Anil K
AK
Sood
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX 77005, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA; Department of Bioengineering, Rice University, Houston, TX 77005, USA. Electronic address: deepak.nagrath@rice.edu.
Deepak
D
Nagrath
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D002244:Carbon / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D006801:Humans; D055442:Metabolome; D008819:Mice, Nude; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D009584:Nitrogen / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism; D017154:Stromal Cells / Q000201:enzymology; D059016:Tumor Microenvironment; D015854:Up-Regulation
D000596:Amino Acids; D009711:Nucleotides; D002244:Carbon; D001219:Aspartate Aminotransferases; D005974:Glutamate-Ammonia Ligase; D009584:Nitrogen