Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia.
Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia.
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DOI：
10.1371/journal.pgen.1002229
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发表时间：
2011-08
期刊：
影响因子：
4.5
通讯作者：
Chi JT
中科院分区：
文献类型：
--
作者：
Kung HN;Marks JR;Chi JT
虽然不同细胞之间存在代谢谱的显著变化，但在这种细胞类型特异性代谢表型和营养需求的遗传调控方面了解甚少。虽然许多癌细胞依赖于外源性谷氨酰胺存活以证明谷氨酰胺代谢的治疗靶向是合理的，但谷氨酰胺依赖性的机制以及这种谷氨酰胺靶向策略在癌症中的可能响应和抗性在很大程度上是未知的。在这项研究中，我们发现了与乳腺分化相关的乳腺肿瘤亚型之间谷氨酰胺依赖性的系统性变化：基底型而不是腔型乳腺细胞更依赖谷氨酰胺，可能对谷氨酰胺靶向治疗敏感。腔型细胞的谷氨酰胺非依赖性与谷氨酰胺合成酶（GS）的谱系特异性表达机制相关。管腔细胞也可以在没有谷氨酰胺的共培养物中拯救基底细胞，表明乳腺导管内谷氨酰胺共生的潜力。GS的管腔特异性表达由GATA 3直接诱导并抑制谷氨酰胺酶的表达。这种独特的谷氨酰胺依赖性和代谢共生与乳腺分化程序期间GS和谷氨酰胺独立性的获得相结合。了解控制不同代谢模式的遗传电路与不同细胞和生物体之间的许多共生关系有关。此外，GS预测肿瘤中谷氨酰胺代谢和依赖模式的能力对于合理设计和应用谷氨酰胺和其他代谢途径靶向治疗也至关重要。不同类型的细胞有不同的方式利用营养素和产生能量，从而导致不同的营养需求。这种细胞类型特异性代谢差异与许多生物过程相关，并促使不同细胞和生物体之间的共生。例如，由于谷氨酰胺合成能力的不同，谷氨酰胺共生是一种公认的现象。在人类癌症中，谷氨酰胺也被认为是一种重要和必需的营养素，称为谷氨酰胺成瘾。但人们对谷氨酰胺成瘾在不同细胞来源的不同肿瘤中的变化知之甚少，这阻碍了个性化的治疗策略。在这里，我们发现基底型乳腺癌细胞对谷氨酰胺缺乏敏感，而管腔型乳腺癌细胞则不敏感。管腔细胞特异性谷氨酰胺不依赖性由赋予合成谷氨酰胺能力的谷氨酰胺合成酶的表达引起。谷氨酰胺合成酶还抑制谷氨酰胺酶，并有助于维持乳腺癌细胞中谷氨酰胺合成酶和谷氨酰胺酶的极化表达。总的来说，这些数据说明了乳腺分化程序和独特的营养需求之间的相互作用，这可能为基底型乳腺癌提供新的治疗方法。
Although significant variations in the metabolic profiles exist among different cells, little is understood in terms of genetic regulations of such cell type–specific metabolic phenotypes and nutrient requirements. While many cancer cells depend on exogenous glutamine for survival to justify the therapeutic targeting of glutamine metabolism, the mechanisms of glutamine dependence and likely response and resistance of such glutamine-targeting strategies among cancers are largely unknown. In this study, we have found a systematic variation in the glutamine dependence among breast tumor subtypes associated with mammary differentiation: basal- but not luminal-type breast cells are more glutamine-dependent and may be susceptible to glutamine-targeting therapeutics. Glutamine independence of luminal-type cells is associated mechanistically with lineage-specific expression of glutamine synthetase (GS). Luminal cells can also rescue basal cells in co-culture without glutamine, indicating a potential for glutamine symbiosis within breast ducts. The luminal-specific expression of GS is directly induced by GATA3 and represses glutaminase expression. Such distinct glutamine dependency and metabolic symbiosis is coupled with the acquisition of the GS and glutamine independence during the mammary differentiation program. Understanding the genetic circuitry governing distinct metabolic patterns is relevant to many symbiotic relationships among different cells and organisms. In addition, the ability of GS to predict patterns of glutamine metabolism and dependency among tumors is also crucial in the rational design and application of glutamine and other metabolic pathway targeted therapies. Different types of cells have distinct ways of utilizing nutrients and generating energy, thus resulting in distinct nutrient needs. Such cell type–specific metabolic differences are associated with many biological processes and force the symbiosis between different cells and organisms. For example, glutamine symbiosis is a well-recognized phenomenon due to different glutamine synthesis ability. In human cancers, glutamine is also recognized as an important and essential nutrient, termed glutamine addiction. But very little is known about how glutamine addiction varies among different tumors of diverse cellular origins, which hinders personalized therapeutic strategies. Here, we found that basal-type breast cancer cells were sensitive to glutamine deprivation while luminal-type breast cancer cells were not. Luminal cell–specific glutamine independence results from expression of glutamine synthetase conferring the ability to synthesize glutamine. Glutamine synthetase also represses glutaminase and contributes to the maintenance of the polarized expression of glutamine synthetase and glutaminase among breast cancer cells. Collectively, these data illustrate cross-talk between mammary differentiation programs and unique nutrient requirements, which may offer novel therapeutics for basal-type breast cancers.
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DOI：
10.1186/bcr2899
发表时间：
2011-06-07
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Gatza ML;Kung HN;Blackwell KL;Dewhirst MW;Marks JR;Chi JT
通讯作者：
Chi JT
DOI：
10.1073/pnas.0912708107
发表时间：
2010-04-13
影响因子：
11.1
作者：
Gatza, Michael L.;Lucas, Joseph E.;Nevins, Joseph R.
通讯作者：
Nevins, Joseph R.
影响因子：
7.1
作者：
Brosnan, Margaret E.;Brosnan, John T.
通讯作者：
Brosnan, John T.
DOI：
10.1073/pnas.1434429100
发表时间：
2003-09-16
影响因子：
11.1
作者：
Chi, JT;Chang, HY;Brown, PO
通讯作者：
Brown, PO
影响因子：
4.5
作者：
Chen JL;Lucas JE;Schroeder T;Mori S;Wu J;Nevins J;Dewhirst M;West M;Chi JT
通讯作者：
Chi JT