近日，美国哈佛医学院Raul Mostoslavsky研究小组发现谷胱甘肽-S-转移酶Gstt1推动转移性癌症的生存和扩散。2024年6月11日出版的《自然—细胞生物学》发表了这项成果。

识别转移性癌细胞的适应机制一直是治疗转移性疾病中的一个难题，特别是在胰腺癌中。

一项针对转移性细胞的功能缺失shRNA筛选发现，谷胱甘肽-S-转移酶家族成员Gstt1在扩散和转移中具有独特的必要性，但对原发肿瘤的生长则无关紧要。Gstt1在潜伏的散播性肿瘤细胞（DTCs）中表达，并在现有转移灶中的一部分缓慢增殖的细胞内保留，其抑制会导致转移性肿瘤的完全消退。这种独特的Gstt1高表达群体高度具有转移性，并保留缓慢增殖表型、上皮-间质转化特征和DTC特性，而相比之下Gstt1低表达群体则不具有这些特性。

机制研究表明，在这一亚群的癌细胞中，Gstt1通过结合和谷胱甘肽修饰细胞内的纤维连接蛋白，进而促进其分泌并沉积到转移微环境中，从而维持转移。他们鉴定了Gstt1作为转移的介质，强调了异质性及其对转移性肿瘤微环境的影响的重要性。

附：英文原文

Title: The glutathione S-transferase Gstt1 drives survival and dissemination in metastases

Author: Ferrer, Christina M., Cho, Hyo Min, Boon, Ruben, Bernasocchi, Tiziano, Wong, Lai Ping, Cetinbas, Murat, Haggerty, Elizabeth R., Mitsiades, Irene, Wojtkiewicz, Gregory R., McLoughlin, Daniel E., Aboushousha, Reem, Abdelhamid, Hend, Kugel, Sita, Rheinbay, Esther, Sadreyev, Ruslan, Juric, Dejan, Janssen-Heininger, Yvonne M. W., Mostoslavsky, Raul

Issue&Volume: 2024-06-11

Abstract: Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial–mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.

DOI: 10.1038/s41556-024-01426-7

Source: https://www.nature.com/articles/s41556-024-01426-7