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.
摘要：
确定转移性癌细胞的适应性机制仍然是治疗转移性疾病的一个难以捉摸的问题。特别是在胰腺癌（胰腺腺癌，PDA)。在转移来源的细胞中进行功能丧失shRNA靶向筛选，鉴定出谷胱甘肽S-转移酶超家族成员Gstt1，作为传播和转移的独特要求，但对于原发性肿瘤的生长是不必要的。Gstt1在潜伏播散性肿瘤细胞（DTC）中表达，保留在现有转移的慢循环细胞亚群中，其抑制导致大转移性肿瘤的完全消退。这种独特的Gstt1high群体是高度转移性的，并保留了缓慢循环的表型，与Gstt1low人群相比，上皮-间质转化特征和DTC特征。机制研究表明，在这一癌细胞亚群中，Gstt1通过结合和谷胱甘肽修饰细胞内纤连蛋白维持转移，反过来促进其分泌和沉积到转移性微环境中。我们确定Gstt1是转移的介质，强调异质性的重要性及其对转移性肿瘤微环境的影响。
