Details

Autor(en) / Beteiligte

• Yang, Lifeng
• Achreja, Abhinav
• Yeung, Tsz-Lun
• Mangala, Lingegowda S.
• Jiang, Dahai
• Han, Cecil
• Baddour, Joelle
• Marini, Juan C.
• Ni, Joseph
• Nakahara, Ryuichi
• Wahlig, Stephen
• Chiba, Lisa
• Kim, Sun Hye
• Morse, Joshua
• Pradeep, Sunila
• Nagaraja, Archana Sidalaghatta
• Haemmerle, Monika
• Kyunghee, Noh
• Derichsweiler, Mathew
• Plackemeier, Thomas
• Mercado-Uribe, Imelda
• Lopez-Berestein, Gabriel
• Moss, Tyler
• Ram, Prahlad T.
• Liu, Jinsong
• Lu, Xiongbin
• Mok, Samuel C.
• Sood, Anil K.
• Nagrath, Deepak

Titel

Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth

Ist Teil von

• Cell metabolism, 2016-11, Vol.24 (5), p.685-700

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• 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. [Display omitted] •CAFs have an upregulated glutamine anabolic pathway compared to NOFs•CAFs harness atypical carbon and nitrogen sources for glutamine synthesis•Crosstalk between stromal-epithelial cells augments dysregulated metabolism in CAFs•Targeting stromal GS in an orthotopic ovarian cancer model induces tumor regression Yang et al. reveal that cancer-associated fibroblasts boost glutamine production by harnessing carbon and nitrogen from atypical nutrient sources to maintain cancer cell growth when glutamine is scarce. Co-targeting stromal glutamine synthetase and cancer cell glutaminase disrupts this metabolic crosstalk, inducing tumor regression in an ovarian carcinoma mouse model.