Single-cell resolved imaging reveals intra-tumor heterogeneity in glycolysis, transitions between metabolic states, and their regulatory mechanisms.
Single-cell resolved imaging reveals intra-tumor heterogeneity in glycolysis, transitions between metabolic states, and their regulatory mechanisms.
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单细胞分辨成像揭示了肿瘤内糖酵解的异质性、代谢状态之间的转换及其调节机制。
DOI：
10.1016/j.celrep.2021.108750
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发表时间：
2021-02-16
期刊：
影响因子：
8.8
通讯作者：
Sahai E
中科院分区：
文献类型：
--
作者：
Kondo H;Ratcliffe CDH;Hooper S;Ellis J;MacRae JI;Hennequart M;Dunsby CW;Anderson KI;Sahai E
已经提出代谢状态的细胞间异质性影响许多癌症表型，包括对靶向治疗的反应。在这里，我们跟踪单个PIK 3CA突变乳腺癌细胞中代谢状态的转变和遗传性，识别非遗传性糖酵解异质性，并建立在依赖于批量分析的方法所获得的观察结果的基础上。在体外和肿瘤中使用荧光生物传感器，我们已经确定了不同的细胞亚群，其糖酵解和线粒体代谢受磷脂酰肌醇3-激酶（PI 3 K）信号转导，布罗莫结构域活性和细胞拥挤效应的组合调节。肌动蛋白切割蛋白cofilin以及PI 3 K调节葡萄糖代谢的快速变化，而用布罗莫结构域抑制剂处理缓慢消除糖酵解活性不依赖于PI 3 K的细胞亚群。我们展示了布罗莫结构域功能和PI 3 K信号传导，沿着肌动蛋白重塑，如何独立调节糖酵解，以及靶向这些途径如何影响不同的癌细胞亚群。葡萄糖生物传感器揭示体内细胞间代谢异质性单细胞剂量反应曲线揭示PI 3 K与糖酵解的可变偶联Cofilin偶联增加细胞密度以代谢变化的调节代谢状态通过有丝分裂可遗传Kondo et al.通过使用生物传感器揭示乳腺癌的代谢异质性，包括PI 3 K与糖酵解的可变偶联。葡萄糖水平通过cofilin与细胞密度相关，从而能够增加迁移细胞的摄取。高糖细胞在没有丙酮酸的情况下生长缓慢，但被其他癌细胞或基质成纤维细胞拯救。
Inter-cellular heterogeneity in metabolic state has been proposed to influence many cancer phenotypes, including responses to targeted therapy. Here, we track the transitions and heritability of metabolic states in single PIK3CA mutant breast cancer cells, identify non-genetic glycolytic heterogeneity, and build on observations derived from methods reliant on bulk analyses. Using fluorescent biosensors in vitro and in tumors, we have identified distinct subpopulations of cells whose glycolytic and mitochondrial metabolism are regulated by combinations of phosphatidylinositol 3-kinase (PI3K) signaling, bromodomain activity, and cell crowding effects. The actin severing protein cofilin, as well as PI3K, regulates rapid changes in glucose metabolism, whereas treatment with the bromodomain inhibitor slowly abrogates a subpopulation of cells whose glycolytic activity is PI3K independent. We show how bromodomain function and PI3K signaling, along with actin remodeling, independently modulate glycolysis and how targeting these pathways affects distinct subpopulations of cancer cells. Glucose biosensor reveals inter-cellular metabolic heterogeneity in vivo Single-cell dose response curves reveal variable coupling of PI3K to glycolysis Regulation of cofilin couples increasing cell density to metabolic changes Metabolic state is heritable through mitosis Kondo et al. reveal metabolic heterogeneity in breast cancer by using biosensors, including variable coupling of PI3K to glycolysis. Glucose levels are linked to cell density by cofilin, enabling increased uptake by migrating cells. High-glucose cells grow slowly without pyruvate but are rescued by other cancer cells or stromal fibroblasts.
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影响因子：
50.3
作者：
Chae YC;Vaira V;Caino MC;Tang HY;Seo JH;Kossenkov AV;Ottobrini L;Martelli C;Lucignani G;Bertolini I;Locatelli M;Bryant KG;Ghosh JC;Lisanti S;Ku B;Bosari S;Languino LR;Speicher DW;Altieri DC
通讯作者：
Altieri DC
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
3.3
作者：
Kim, Jun-Sub;Huang, Timothy Y.;Bokoch, Gary M.
通讯作者：
Bokoch, Gary M.
影响因子：
29
作者：
Bertero T;Oldham WM;Grasset EM;Bourget I;Boulter E;Pisano S;Hofman P;Bellvert F;Meneguzzi G;Bulavin DV;Estrach S;Feral CC;Chan SY;Bozec A;Gaggioli C
通讯作者：
Gaggioli C
影响因子：
3.7
作者：
Kanazawa S;Fujiwara T;Matsuzaki S;Shingaki K;Taniguchi M;Miyata S;Tohyama M;Sakai Y;Yano K;Hosokawa K;Kubo T
通讯作者：
Kubo T