Cancer-associated fibroblast-derived ROR2 induces WNT/PCP activation and polarized migration in receiving gastric cancer cells
Cancer-associated fibroblast-derived ROR2 induces WNT/PCP activation and polarized migration in receiving gastric cancer cells
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癌症相关成纤维细胞衍生的 ROR2 在接受胃癌细胞中诱导 WNT/PCP 激活和极化迁移
DOI：
10.1101/2022.04.07.487474
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Rogers S
中科院分区：
文献类型：
--
作者：
Rogers S
在许多研究中，肿瘤间质环境中的骨髓间充质干细胞和癌症相关成纤维细胞与癌症进展有关。这些成纤维细胞为肿瘤细胞提供信号因子，促进其增殖、存活、侵袭和转移。影响肿瘤细胞行为的一个信号通路是胃癌中的WNT/平面细胞极性(PCP)信号。在这里，我们发现胃肿瘤细胞系AGS可以对PCP配体Wnt5A产生反应，然而，真正的WNT/PCP受体ROR2的表达水平非常低。同时，我们发现CAF呈现长丝足，其ROR2的表达水平明显高于正常胃成纤维细胞。通过高分辨率成像，我们观察到含有ROR2和WNT5A的复合体从CAF直接转移到胃癌细胞。在受体细胞中，ROR2的转移量与JNK信号相关，表明直接需要受体的转移量。与野生型CAF相比，AGS与表达显性-负性ROR2的CAF共培养时，肌动蛋白的极化和迁移减少。此外，在斑马鱼活体模型中观察到通过旁分泌ROR2转移诱导迁移。这些意想不到的发现展示了Wnt受体从信号产生细胞到接收细胞的直接转移中的新角色，并解释了低水平表达ROR2的胃癌细胞可以对高Wnt5A肿瘤微环境做出反应的机制。
Bone marrow-derived mesenchymal stem cells and cancer-associated fibroblasts in the tumor-stromal environment have been linked to cancer progression in many studies. These fibroblasts provide signaling factors to the tumor cells that promote proliferation, survival, invasion, and metastasis. One signaling pathway influencing tumor cell behavior is the WNT/Planar Cell Polarity (PCP) signaling in gastric cancer. Here, we show that the gastric tumor cell line, AGS, can respond to the PCP ligand WNT5A, however, express a very low level of the bona-fide WNT/PCP receptor, ROR2. At the same time, we find that CAF display long filopodia and had significantly higher levels of ROR2 than normal gastric fibroblasts. By high-resolution imaging, we observe a direct, cytoneme-mediated transfer of a complex containing ROR2 and WNT5A from CAF to the gastric cancer cells. The amount of ROR2 transferred correlated with JNK signaling in receiving cells, showing a direct requirement for receptor transfer. Co-culture of AGS with CAF expressing a dominant-negative form of ROR2 exhibited reduced actin polarization and migration compared to wild-type CAF. Furthermore, induction of migration via paracrine ROR2 transfer was observed in a zebrafishin vivomodel. These unexpected findings demonstrate a fresh role in the direct transfer of a Wnt receptor from a signal-producing cell to a receiving cell and explain the mechanism by which gastric cancer cells expressing low levels of ROR2 can respond to a WNT5A-high tumor microenvironment.
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影响因子：
7.3
作者：
Sally Rogers;S. Scholpp
通讯作者：
Sally Rogers;S. Scholpp
影响因子：
4.7
作者：
Holmberg, Chris;Quante, Michael;Varro, Andrea
通讯作者：
Varro, Andrea
DOI：
10.1152/ajpgi.00443.2015
发表时间：
2016-05
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
--
作者：
Liyi Wang;I. Steele;J. D. Kumar;R. Dimaline;P. Jithesh;L. Tiszlavicz;Z. Reisz;G. Dockray;A. Varró
通讯作者：
Liyi Wang;I. Steele;J. D. Kumar;R. Dimaline;P. Jithesh;L. Tiszlavicz;Z. Reisz;G. Dockray;A. Varró
DOI：
10.1126/science.1244624
发表时间：
2014-02-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Roy S;Huang H;Liu S;Kornberg TB
通讯作者：
Kornberg TB
影响因子：
16.6
作者：
Stanganello, Eliana;Hagemann, Anja I. H.;Scholpp, Steffen
通讯作者：
Scholpp, Steffen