Tumor-associated macrophage-derived GDNF promotes gastric cancer liver metastasis via a GFRA1-modulated autophagy flux.
Tumor-associated macrophage-derived GDNF promotes gastric cancer liver metastasis via a GFRA1-modulated autophagy flux.
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DOI：
10.1007/s13402-022-00751-z
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发表时间：
2023-04
影响因子：
6.6
通讯作者：
Zhang, Zizhen
中科院分区：
文献类型：
--
作者：
Ni, Bo;He, Xuan;Zhang, Yeqian;Wang, Zeyu;Dong, Zhongyi;Xia, Xiang;Zhao, Gang;Cao, Hui;Zhu, Chunchao;Li, Qing;Liu, Jiahua;Chen, Huimin;Zhang, Zizhen
肝转移是胃癌患者的致命恶性肿瘤，严重影响其预后。然而，到目前为止，很少有研究被设计来确定其形成过程中的驱动分子，除了筛选证据暂停之前，他们的功能或机制。在这里，我们的目的是调查一个关键的驱动事件的侵袭性边缘的肝转移。转移性GC组织微阵列用于探索肝转移形成期间的恶性事件，随后评估胶质细胞源性神经营养因子（GDNF）和GDNF家族受体α 1（GFRA 1）的表达模式。它们的致癌功能通过体外和体内的功能丧失和获得研究来确定，并通过拯救实验来验证。进行了多项细胞生物学研究，以确定潜在的机制。在侵袭性边缘，GFRA 1被确定为在肝转移形成期间参与细胞存活的关键分子，并且我们发现其致癌作用依赖于肿瘤相关巨噬细胞（TAM）衍生的GDNF。此外，我们还发现GDNF-GFRA 1轴通过调节溶酶体功能和自噬通量来保护肿瘤细胞免受代谢应激下的凋亡，并以不依赖RET的非经典方式参与调节胞浆钙离子信号传导。从我们的数据中，我们得出结论，TAMs，归巢周围转移巢，诱导自噬流量的GC细胞，并促进发展的肝转移，通过GDNF-GFRA 1信号。这有望提高对转移性胃癌发病机制的理解，并为转移性胃癌患者的治疗提供新的研究方向和转化策略。在线版本包含补充材料，可通过10.1007/s13402-022-00751-z获得。
Liver metastasis, a lethal malignancy of gastric cancer (GC) patients, execrably impairs their prognosis. As yet, however, few studies have been designed to identify the driving molecules during its formation, except screening evidence pausing before their functions or mechanisms. Here, we aimed to survey a key driving event within the invasive margin of liver metastases. A metastatic GC tissue microarray was used for exploring malignant events during liver-metastasis formation, followed by assessing the expression patterns of glial cell-derived neurotrophic factor (GDNF) and GDNF family receptor alpha 1 (GFRA1). Their oncogenic functions were determined by both loss- and gain-of-function studies in vitro and in vivo, and validated by rescue experiments. Multiple cell biological studies were performed to identify the underlying mechanisms. In the invasive margin, GFRA1 was identified as a pivotal molecule involved in cellular survival during liver metastasis formation, and we found that its oncogenic role depends on tumor associated macrophage (TAM)-derived GDNF. In addition, we found that the GDNF-GFRA1 axis protects tumor cells from apoptosis under metabolic stress via regulating lysosomal functions and autophagy flux, and participates in the regulation of cytosolic calcium ion signalling in a RET-independent and non-canonical way. From our data we conclude that TAMs, homing around metastatic nests, induce the autophagy flux of GC cells and promote the development of liver metastasis via GDNF-GFRA1 signalling. This is expected to improve the comprehension of metastatic pathogenesis and to provide a novel direction of research and translational strategies for the treatment of metastatic GC patients. The online version contains supplementary material available at 10.1007/s13402-022-00751-z.
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影响因子：
29
作者：
Kimmelman AC;White E
通讯作者：
White E
POU2F1/miR-4490/USP22轴调节胃癌细胞增殖和转移
DOI：
10.1007/s13402-020-00553-1
发表时间：
2020-12
期刊：
Cellular oncology (Dordrecht, Netherlands)
影响因子：
--
作者：
Xiao Y;Liu S;Li J;Dai W;Tang W;Xiang L;Zhang W;Lin J;Wang J;Wu X;Liu G;Liu Y;Chen Y;Zhu H;Wang Y;Lin Z;Yang Q;Chen T;Sun Y;Li A;Xiong J;Wang J
通讯作者：
Wang J
胃癌来源的间充质基质细胞触发M2巨噬细胞极化，促进胃癌转移和EMT
影响因子：
9
作者：
Li, Wei;Zhang, Xu;Zhao, Shaolin
通讯作者：
Zhao, Shaolin
DOI：
10.1016/s0140-6736(17)33326-3
发表时间：
2018-03-17
期刊：
Lancet (London, England)
影响因子：
--
作者：
Allemani C;Matsuda T;Di Carlo V;Harewood R;Matz M;Nikšić M;Bonaventure A;Valkov M;Johnson CJ;Estève J;Ogunbiyi OJ;Azevedo E Silva G;Chen WQ;Eser S;Engholm G;Stiller CA;Monnereau A;Woods RR;Visser O;Lim GH;Aitken J;Weir HK;Coleman MP;CONCORD Working Group
通讯作者：
CONCORD Working Group
影响因子：
4.3
作者：
Digklia, Antonia;Wagner, Anna Dorothea
通讯作者：
Wagner, Anna Dorothea