Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy.
Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy.
复制标题
DOI：
10.1016/j.cmet.2018.09.012
复制
发表时间：
2019-01-08
期刊：
影响因子：
29
通讯作者：
Gaggioli C
中科院分区：
文献类型：
--
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
细胞外基质（ECM）沉积和细胞代谢的失调通过维持关键生长、侵袭和生存途径的活性来促进肿瘤的侵袭性。然而，ECM的生物物理特性与代谢过程和肿瘤进展相关的机制仍不清楚。在癌细胞和癌相关成纤维细胞（CAF）中，我们发现ECM硬化机制激活糖酵解和谷氨酰胺代谢，从而协调肿瘤生态位内非必需氨基酸的流动。具体来说，我们证明了CAF和癌细胞之间的代谢串扰，其中CAF衍生的天冬氨酸维持癌细胞增殖，而癌细胞衍生的谷氨酸平衡CAF的氧化还原状态，促进ECM重塑。总的来说，我们的研究结果将机械刺激与肿瘤代谢失调联系起来，从而突出了肿瘤内新的代谢网络，其中不同的燃料来源用于促进生长和侵袭性。此外，本研究确定了癌症治疗发展的潜在代谢药物靶点。Bertero等人将癌细胞和癌相关成纤维细胞（CAFs）的细胞外基质（ECM）硬化与肿瘤生态位中YAP/ taz依赖性谷氨酸/天门氨酸串扰联系起来。谷氨酰胺酶和天冬氨酸/谷氨酸转运体SLC1A3在肿瘤中的共同靶向抑制了癌症的进展和转移。
Dysregulation of extracellular matrix (ECM) deposition and cellular metabolism promotes tumor aggressiveness by sustaining the activity of key growth, invasion, and survival pathways. Yet, mechanisms by which biophysical properties of ECM relate to metabolic processes and tumor progression remain undefined. In both cancer cells and carcinomaassociated fibroblasts (CAF), we found that ECM stiffening mechanoactivates glycolysis and glutamine metabolism and thus coordinates non-essential amino acid flux within the tumor niche. Specifically, we demonstrate a metabolic crosstalk between CAF and cancer cells in which CAF-derived aspartate sustains cancer cell proliferation, while cancer cell-derived glutamate balances the redox state of CAF to promote ECM remodeling. Collectively, our findings link mechanical stimuli to dysregulated tumor metabolism and thereby highlight a new metabolic network within tumors in which diverse fuel sources are used to promote growth and aggressiveness. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in cancer. Bertero et al. link extracellular matrix (ECM) stiffening of both cancer cells and carcinoma-associated fibroblasts (CAFs) to metabolic rewiring through a YAP/TAZ-dependent glutamate/aspartate crosstalk in the tumor niche. Pharmacological co-targeting of glutaminase and the aspartate/glutamate transporter SLC1A3 in tumors blunts cancer progression and metastasis.
登录
查看更多内容
影响因子：
82.9
作者：
Davidson SM;Jonas O;Keibler MA;Hou HW;Luengo A;Mayers JR;Wyckoff J;Del Rosario AM;Whitman M;Chin CR;Condon KJ;Lammers A;Kellersberger KA;Stall BK;Stephanopoulos G;Bar-Sagi D;Han J;Rabinowitz JD;Cima MJ;Langer R;Vander Heiden MG
通讯作者：
Vander Heiden MG
Vinculin磷酸化差异地调节了细胞 - 细胞和细胞矩阵粘附处的机械转导。
DOI：
10.1083/jcb.201309092
发表时间：
2014-04-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bays JL;Peng X;Tolbert CE;Guilluy C;Angell AE;Pan Y;Superfine R;Burridge K;DeMali KA
通讯作者：
DeMali KA
影响因子：
7.4
作者：
Heuillet, Maud;Bellvert, Floriant;Portais, Jean-Charles
通讯作者：
Portais, Jean-Charles
影响因子：
5.7
作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.
缺氧介导的 L-2-羟基戊二酸增加可协调对还原应激的代谢反应。
影响因子：
29
作者：
Oldham WM;Clish CB;Yang Y;Loscalzo J
通讯作者：
Loscalzo J