Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth.
Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth.
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靶向肿瘤中的基质谷氨酰胺合成酶破坏肿瘤微环境调节的癌细胞生长
DOI：
10.1016/j.cmet.2016.10.011
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发表时间：
2016-11-08
期刊：
影响因子：
29
通讯作者：
Nagrath D
中科院分区：
文献类型：
--
作者：
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
反应性基质细胞是肿瘤微环境（TME）的组成部分，并与癌细胞相互作用以调节其生长。尽管靶向基质细胞可能是调节TME和癌细胞之间通讯的可行疗法，但鉴定使癌细胞脆弱的基质靶点仍然具有挑战性和难以捉摸。在这里，我们确定了一个以前未认识到的机制，反应性基质细胞的代谢是通过上调谷氨酰胺合成代谢途径重新编程。这种功能失调的基质代谢赋予基质细胞非典型的代谢灵活性和适应性机制，使它们能够利用来自非典型来源的碳和氮，在TME中存在的营养缺乏条件下合成谷氨酰胺。使用卵巢癌的原位小鼠模型，我们发现共靶向间质中的谷氨酰胺合成酶和癌细胞中的谷氨酰胺酶可减少肿瘤重量、结节和转移。我们提出了一种同时靶向肿瘤基质和癌细胞的合成致死方法，以获得理想的治疗效果。Yang等人揭示，当谷氨酰胺缺乏时，癌症相关的成纤维细胞通过利用来自非典型营养源的碳和氮来维持癌细胞生长，从而促进谷氨酰胺的产生。共靶向基质谷氨酰胺合成酶和癌细胞谷氨酰胺酶破坏这种代谢串扰，诱导卵巢癌小鼠模型中的肿瘤消退。
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. 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.
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影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
64.8
作者：
Perera, RushikaM.;Stoykova, Svetlana;Nicolay, Brandon N.;Ross, Kenneth N.;Fitamant, Julien;Boukhali, Myriam;Lengrand, Justine;Deshpande, Vikram;Selig, Martin K.;Ferrone, Cristina R.;Settleman, Jeff;Stephanopoulos, Gregory;Dyson, Nicholas J.;Zoncu, Roberto;Ramaswamy, Sridhar;Haas, Wilhelm;Bardeesy, Nabeel
通讯作者：
Bardeesy, Nabeel
影响因子：
9.9
作者：
Yang, Lifeng;Moss, Tyler;Mangala, Lingegowda S.;Marini, Juan;Zhao, Hongyun;Wahlig, Stephen;Armaiz-Pena, Guillermo;Jiang, Dahai;Achreja, Abhinav;Win, Julia;Roopaimoole, Rajesha;Rodriguez-Aguayo, Cristian;Mercado-Uribe, Imelda;Lopez-Berestein, Gabriel;Liu, Jinsong;Tsukamoto, Takashi;Sood, Anil K.;Ram, Prahlad T.;Nagrath, Deepak
通讯作者：
Nagrath, Deepak
影响因子：
5.7
作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.
DOI：
10.1073/pnas.1307237110
发表时间：
2013-05-28
影响因子：
11.1
作者：
Kamphorst, Jurre J.;Cross, Justin R.;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.