小柯机器人

比利时鲁汶大学癌症生物学中心Sarah-Maria Fendt团队近期取得重要工作进展。他们研究发现PHGDH的异质性增强了癌细胞的传播和转移能力。该项研究成果2022年5月18日在线发表于《自然》杂志上。

在这里，研究人员发现磷酸甘油酸脱氢酶 (PHGDH) 的缺失会增强转移性传播。具体而言，他们发现乳腺癌患者原发性肿瘤中PHGDH的异质或低表达与无转移生存时间缩短有关。在小鼠中，循环肿瘤细胞和早期转移病灶富含Phgdh^low癌细胞，在原发性肿瘤中沉默Phgdh会增加转移形成。

从机制上讲，Phgdh与糖酵解酶磷酸果糖激酶相互作用，并且这种相互作用的丧失激活了己糖胺-唾液酸途径，该途径为蛋白质糖基化提供了前体。因此，会发生异常的蛋白质糖基化，包括增加整合素αvβ3的唾液酸化，从而增强细胞迁移和侵袭。抑制唾液酸化可抵消Phgdh^low癌细胞的转移能力。总之，虽然PHGDH的催化活性支持癌细胞增殖，但低PHGDH蛋白表达非催化增强了癌细胞的扩散和转移形成。因此，原发性肿瘤中PHDGH异质性的存在可以被认为是肿瘤侵袭性的标志。

据介绍，癌症转移需要细胞程序的瞬时激活，从而能够在远处器官中传播和播种。遗传、转录和翻译异质性促成了这一动态过程。肿瘤中的代谢异质性也已被观察到，但其在癌症进展中的作用较少被探讨。

附：英文原文

Title: PHGDH heterogeneity potentiates cancer cell dissemination and metastasis

Author: Rossi, Matteo, Altea-Manzano, Patricia, Demicco, Margherita, Doglioni, Ginevra, Bornes, Laura, Fukano, Marina, Vandekeere, Anke, Cuadros, Alejandro M., Fernndez-Garca, Juan, Riera-Domingo, Carla, Jauset, Cristina, Planque, Mlanie, Alkan, H. Furkan, Nittner, David, Zuo, Dongmei, Broadfield, Lindsay A., Parik, Sweta, Pane, Antonino Alejandro, Rizzollo, Francesca, Rinaldi, Gianmarco, Zhang, Tao, Teoh, Shao Thing, Aurora, Arin B., Karras, Panagiotis, Vermeire, Ines, Broekaert, Dorien, Elsen, Joke Van, Knott, Maximilian M. L., Orth, Martin F., Demeyer, Sofie, Eelen, Guy, Dobrolecki, Lacey E., Bassez, Ayse, Brussel, Thomas Van, Sotlar, Karl, Lewis, Michael T., Bartsch, Harald, Wuhrer, Manfred, Veelen, Peter van, Carmeliet, Peter, Cools, Jan, Morrison, Sean J., Marine, Jean-Christophe, Lambrechts, Diether, Mazzone, Massimiliano, Hannon, Gregory J., Lunt, Sophia Y., Grnewald, Thomas G. P., Park, Morag, Rheenen, Jacco van, Fendt, Sarah-Maria

Issue&Volume: 2022-05-18

Abstract: Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdhlow cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine–sialic acid pathway, which provides precursors for protein glycosylation. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin αvβ3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlow cancer cells. In conclusion, although the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumours could be considered a sign of tumour aggressiveness.

DOI: 10.1038/s41586-022-04758-2

Source: https://www.nature.com/articles/s41586-022-04758-2

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