Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities.
Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities.
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三阴性乳腺癌细胞的代谢分析揭示了代谢脆弱性。
DOI：
10.1186/s40170-017-0168-x
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发表时间：
2017
影响因子：
5.9
通讯作者：
Graveel CR
中科院分区：
文献类型：
--
作者：
Lanning NJ;Castle JP;Singh SJ;Leon AN;Tovar EA;Sanghera A;MacKeigan JP;Filipp FV;Graveel CR
在乳腺癌中，三阴性乳腺癌（TNBC）亚型的预后最差，没有批准的靶向治疗，只有标准化疗作为全身治疗的支柱。癌症进展中独特的代谢变化提供了创新的治疗机会。受体酪氨酸激酶（RTK）、表皮生长因子受体（EGFR）和MET受体在TNBC中高度表达，成为两种有前途的治疗靶点。RTK信号通过增加葡萄糖消耗并随后将葡萄糖碳源转移到支持肿瘤发生所必需的代谢途径中来深刻地改变细胞代谢。因此，TNBC亚型的详细代谢谱及其对酪氨酸激酶抑制剂的反应可以鉴定治疗敏感性。我们使用气相色谱质谱法定量了代表多种TNBC亚型的TNBC细胞系的代谢谱。此外，我们对MDA-MB-231、MDA-MB-468、Hs578T和HCC 70细胞系进行了基础和最大糖酵解和线粒体氧化速率的代谢通量分析。在存在和不存在MET抑制剂INC 280/capmatinib和EGFR抑制剂厄洛替尼的情况下进行代谢池大小和通量测量。此外，测定了这些细胞对核心代谢途径调节剂的敏感性。此外，我们注释了限速代谢酶文库，并与MET或EGFR抑制剂组合进行siRNA筛选以验证协同效应。TNBC细胞系模型在基础和最大代谢率以及对RTK和代谢途径抑制剂的反应方面显示出显著的代谢异质性。代谢扰动的综合系统生物学分析、组合的siRNA和酪氨酸激酶抑制剂筛选鉴定了TCA循环和脂肪酸途径的核心集合，其扰动使TNBC细胞对受体酪氨酸激酶的小分子靶向敏感。类似于在TNBC中观察到的基因组异质性，我们的结果揭示了TNBC亚型之间的代谢异质性，并表明理解代谢谱和药物反应可能在靶向TNBC亚型和鉴定TNBC患者的治疗敏感性方面证明是有价值的。代谢途径的扰动使TNBC对受体酪氨酸激酶的抑制敏感。这种代谢脆弱性为TNBC患者的有效治疗靶向提供了希望。本文的在线版本（doi：10.1186/s40170 - 017 - 0168-x）包含补充材料，可供授权用户使用。
Among breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities. We quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects. TNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases. Similar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients. The online version of this article (doi:10.1186/s40170-017-0168-x) contains supplementary material, which is available to authorized users.
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影响因子：
4.3
作者：
Filipp FV;Ratnikov B;De Ingeniis J;Smith JW;Osterman AL;Scott DA
通讯作者：
Scott DA
影响因子：
11.5
作者：
De Rosa, Viviana;Iommelli, Francesca;Del Vecchio, Silvana
通讯作者：
Del Vecchio, Silvana
影响因子：
4.4
作者：
Jiang, Tingting;Shi, Weiwei;Hatzis, Christos
通讯作者：
Hatzis, Christos
DOI：
10.1186/bcr3472
发表时间：
2013
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Choi J;Kim DH;Jung WH;Koo JS
通讯作者：
Koo JS
肿瘤微环境产生的酸度驱动局部侵袭。
影响因子：
11.2
作者：
Estrella V;Chen T;Lloyd M;Wojtkowiak J;Cornnell HH;Ibrahim-Hashim A;Bailey K;Balagurunathan Y;Rothberg JM;Sloane BF;Johnson J;Gatenby RA;Gillies RJ
通讯作者：
Gillies RJ