Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy

Bertero Thomas; Oldham William M.; Grasset Eloise M.; Bourget Isabelle; Boulter Etienne; Pisano Sabrina; Hofman Paul; Bellvert Floriant; Meneguzzi Guerrino; Bulavin Dmitry V; Estrach Soline; Feral Chloe C.; Chan Stephen Y.; Bozec Alexandre; Gaggioli Cedric

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Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy

机译：肿瘤 - 基质力学坐标氨基酸可用性以维持肿瘤生长和恶性肿瘤

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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 carcinoma-associated fibroblasts (CAFs), 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 CAFs 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.

机译：细胞外基质（ECM）沉积和细胞代谢的失调通过维持关键生长，侵袭和存活途径的活性促进肿瘤侵袭性。然而，ECM的生物物理性质与代谢过程和肿瘤进展的机制仍未确定。在癌细胞和癌细胞相关的成纤维细胞（CAF）中，我们发现ECM加强机械激活糖酵解和谷氨酰胺代谢，从而坐标在肿瘤Niche内的非必需氨基酸通量坐标。具体而言，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谷氨酸植物衍生的氧化糖酸盐稳定性，以促进ECM改造。统称，我们的研究结果将机械刺激链接到失调的肿瘤新陈代谢，从而突出了一种新的代谢网络，其中肿瘤中的多样化燃料源用于促进生长和侵袭性。此外，该研究识别癌症治疗发育的潜在代谢药物靶标。

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《Cell metabolism》 |2019年第1期|共27页
作者
Bertero Thomas; Oldham William M.; Grasset Eloise M.; Bourget Isabelle; Boulter Etienne; Pisano Sabrina; Hofman Paul; Bellvert Floriant; Meneguzzi Guerrino; Bulavin Dmitry V; Estrach Soline; Feral Chloe C.; Chan Stephen Y.; Bozec Alexandre; Gaggioli Cedric;
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作者单位

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Harvard Med Sch Brigham &

Womens Hosp Dept Med Div Pulm &

Crit Care Med Boston MA 02115 USA;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Toulouse INSA INRA LISBP CNRS Toulouse France;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Ctr Antoine Lacassag;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Pittsburgh Ctr Pulm Vasc Biol &

Med Pittsburgh Heart Lung Blood &

Vasc Med Inst Div Cardiol;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

Univ Cote Azur Inst Res Canc &

Aging Nice IRCAN CNRS UMR7284 INSERM U1081 Nice France;

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正文语种 eng
中图分类内分泌腺疾病及代谢病;
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专利

1. Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy [J] . Bertero Thomas, Oldham William M., Grasset Eloise M., Cell metabolism . 2019,第1期

机译：肿瘤 - 基质力学坐标氨基酸可用性以维持肿瘤生长和恶性肿瘤
2. Adaptation of in vivo amino acid kinetics facilitates increased amino acid availability for fetal growth in adolescent and adult pregnancies alike [J] . Alan A. Jackson, Asha V. Badaloo, Farook Jahoor, The British Journal of Nutrition . 2014,第11期

机译：体内氨基酸动力学的适应性促进了增加青春期和成年孕妇胎儿的氨基酸可用性
3. Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma. [J] . Mazzocca A, Fransvea E, Dituri Hepatology: Official Journal of the American Association for the Study of Liver Diseases . 2010,第2期

机译：通过抑制转化生长因子β来下调结缔组织生长因子，从而阻断了肝细胞癌中的肿瘤基质干扰和肿瘤进展。
4. Formation and sustained-dissociation of antitumor platinum-loaded micelles regulated by secondary structure of poly(amino acids) in their core [C] . Yuki Mochida, Albertini Francesco, Horacio Cabral, World biomaterials congress . 2012

机译：抗肿瘤铂负载胶束的形成和持续解离受其核心中聚氨基酸二级结构调控
5. SOME METABOLIC ANOMALIES OF MALIGNANCY; STUDIES ON SOME TUMOR-HOST RELATIONSHIPS WITH REFERENCE TO AMINO ACID AND PROTEIN METABOLISM IN RATSBEARING THE WALKER-256 TUMOR [D] . ITIABA, KIBE -1

机译：代谢不良的某些代谢异常； WALKER-256肿瘤大鼠中与氨基酸和蛋白质代谢相关的一些肿瘤-宿主关系的研究
6. CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression [O] . Sara Cano-Crespo, Josep Chillarón, Alexandra Junza, -1

机译：CD98hc（SLC3A2）维持氨基酸和核苷酸的可用性促进细胞周期进程
7. Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy [O] . Thomas Bertero, William M. Oldham, Eloise M. Grasset, 2019

机译：肿瘤 - 基质力学坐标氨基酸可用性以维持肿瘤生长和恶性肿瘤
8. Modulation of Anaplastic Lymphoma Kinase Upon Tumor-Stroma Interaction and Its Implications for Tumor Growth and Metastasis in Breast Cancer [R] . Stoica, E. 2005

机译：间变性淋巴瘤激酶对肿瘤 - 基质相互作用的调节作用及其对乳腺癌肿瘤生长和转移的影响

Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy

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