Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.
Nat Commun. 2020 Mar 10;11(1):1290. doi: 10.1038/s41467-020-15104-3.
Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.
新出现的证据表明,癌症相关成纤维细胞(CAFs)可以调节癌细胞代谢,但具体机制尚不清楚。在这里,我们表明 CAFs 通过受 FAK 控制的途径调节恶性细胞代谢。在乳腺癌和胰腺癌患者中,我们发现 FAK 表达水平低,特别是在基质区室中,预示着总生存期缩短。在小鼠中,在 CAFs 的一个亚群中耗尽 FAK 会调节旁分泌信号,从而增加恶性细胞的糖酵解和肿瘤生长。在我们的小鼠模型中的蛋白质组学和磷酸蛋白质组学分析确定了代谢改变,这些改变在低基质 FAK 的患者中反映在转录组水平上。从机制上讲,我们证明 CAFs 中的 FAK 耗竭会增加趋化因子的产生,这些趋化因子通过癌细胞上的 CCR1/CCR2 激活蛋白激酶 A,从而增强恶性细胞的糖酵解。我们的数据揭示了基质成纤维细胞调节癌症细胞代谢的机制,这些机制独立于癌症细胞中的基因突变。
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