Location: Children's Nutrition Research CenterTitle: Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth
|YANG, LIFENG - Rice University|
|ACHREJA, ABHINAV - Rice University|
|YEUNG, TSZ-LUN - Md Anderson Cancer Center|
|MANGALA, LINGEGOWDA - Md Anderson Cancer Center|
|JIANG, DAHAI - Md Anderson Cancer Center|
|HAN, CECIL - Md Anderson Cancer Center|
|BADDOUR, JOELLE - Rice University|
|MARINI, JUAN - Baylor College Of Medicine|
Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/1/2016
Publication Date: 11/8/2016
Citation: Yang, L., Achreja, A., Yeung, T., Mangala, L.S., Jiang, D., Han, C., Baddour, J., Marini, J.C. 2016. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metabolism. 24(5):685-700.
Interpretive Summary: This research demonstrated that non-cancer cells surrounding a tumor modify their metabolism and produce nutrients that are used by the tumor for its growth. Targeting these metabolic pathways disrupts this intercellular crosstalk and induces tumor regression. This work suggests that nutrient supply to different tissues is more complex than previously thought. A better understanding of these processes may allow nutrients to be targeted to specific organs.
Technical 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.