In vivo metabolic imaging identifies lipid vulnerability in a preclinical model of Her2+/Neu breast cancer residual disease and recurrence.
In vivo metabolic imaging identifies lipid vulnerability in a preclinical model of Her2+/Neu breast cancer residual disease and recurrence.
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DOI：
10.1038/s41523-022-00481-3
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发表时间：
2022-09-26
影响因子：
5.9
通讯作者：
Ramanujam, Nirmala
中科院分区：
文献类型：
--
作者：
Madonna, Megan C.;Duer, Joy E.;McKinney, Brock J.;Sunassee, Enakshi D.;Crouch, Brian T.;Ilkayeva, Olga;Hirschey, Matthew D.;Alvarez, James, V;Ramanujam, Nirmala
逃避治疗的复发癌细胞是乳腺癌患者死亡的主要原因。这种风险对于人类表皮生长因子受体2(Her2)过度表达的女性来说是很高的。与原发肿瘤细胞相比，存活的细胞可以依赖不同的底物来产生能量。在这里，我们利用纵向荧光显微镜研究了多西环素诱导的Her2+/Neu乳腺癌模型中与肿瘤休眠和复发相关的代谢重编程。葡萄糖摄取(2-NBDG)和线粒体膜电位(TMRE)成像代谢表型乳腺肿瘤的退化，休眠和复发。“快速复发”肿瘤(复发时间~55天)，在消退过程中从糖酵解过渡到线粒体代谢，并在复发时持续。“慢复发”肿瘤(复发时间~100天)在复发期间依赖糖酵解和线粒体代谢。在快速复发的肿瘤中，线粒体活性的增加归因于将葡萄糖转变为脂肪酸作为线粒体代谢的主要能量来源。因此，当快速复发的肿瘤接受脂肪酸抑制剂etomoxir的治疗时，肿瘤在消退过程中报告葡萄糖摄取和脂肪合成增加。依托莫西的治疗最终延长了患者的生存时间。我们发现代谢重新编程报告了肿瘤复发的特征，特别是在对可操作靶点至关重要的时间点。代谢重新编程的时间特征在确定潜在治疗的适当时机方面将是至关重要的；即，在回归过程中代谢靶向抑制报告长期治疗益处的概念。
Recurrent cancer cells that evade therapy is a leading cause of death in breast cancer patients. This risk is high for women showing an overexpression of human epidermal growth factor receptor 2 (Her2). Cells that persist can rely on different substrates for energy production relative to their primary tumor counterpart. Here, we characterize metabolic reprogramming related to tumor dormancy and recurrence in a doxycycline-induced Her2+/Neu model of breast cancer with varying times to recurrence using longitudinal fluorescence microscopy. Glucose uptake (2-NBDG) and mitochondrial membrane potential (TMRE) imaging metabolically phenotype mammary tumors as they transition to regression, dormancy, and recurrence. “Fast-recurrence” tumors (time to recurrence ~55 days), transition from glycolysis to mitochondrial metabolism during regression and this persists upon recurrence. “Slow-recurrence” tumors (time to recurrence ~100 days) rely on both glycolysis and mitochondrial metabolism during recurrence. The increase in mitochondrial activity in fast-recurrence tumors is attributed to a switch from glucose to fatty acids as the primary energy source for mitochondrial metabolism. Consequently, when fast-recurrence tumors receive treatment with a fatty acid inhibitor, Etomoxir, tumors report an increase in glucose uptake and lipid synthesis during regression. Treatment with Etomoxir ultimately prolongs survival. We show that metabolic reprogramming reports on tumor recurrence characteristics, particularly at time points that are essential for actionable targets. The temporal characteristics of metabolic reprogramming will be critical in determining the use of an appropriate timing for potential therapies; namely, the notion that metabolic-targeted inhibition during regression reports long-term therapeutic benefit.
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影响因子：
11.2
作者：
Alvarez JV;Belka GK;Pan TC;Chen CC;Blankemeyer E;Alavi A;Karp JS;Chodosh LA
通讯作者：
Chodosh LA
影响因子：
4.5
作者：
Ferrara CT;Wang P;Neto EC;Stevens RD;Bain JR;Wenner BR;Ilkayeva OR;Keller MP;Blasiole DA;Kendziorski C;Yandell BS;Newgard CB;Attie AD
通讯作者：
Attie AD
DOI：
10.1007/978-3-030-35805-1_3
发表时间：
2020-01-01
期刊：
CIRCULATING TUMOR CELLS IN BREAST CANCER METASTATIC DISEASE
影响因子：
--
作者：
Banys-Paluchowski, Malgorzata;Reinhardt, Florian;Fehm, Tanja
通讯作者：
Fehm, Tanja
影响因子：
5.9
作者：
Epstein T;Xu L;Gillies RJ;Gatenby RA
通讯作者：
Gatenby RA
影响因子：
8.8
作者：
Bartlome S;Berry CC
通讯作者：
Berry CC