Cancer-associated fibroblasts influence Wnt/PCP signaling in gastric cancer cells by cytoneme-based dissemination of ROR2.
Cancer-associated fibroblasts influence Wnt/PCP signaling in gastric cancer cells by cytoneme-based dissemination of ROR2.
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DOI：
10.1073/pnas.2217612120
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发表时间：
2023-09-26
影响因子：
11.1
通讯作者：
Scholpp S
中科院分区：
文献类型：
--
作者：
Rogers S;Zhang C;Anagnostidis V;Liddle C;Fishel ML;Gielen F;Scholpp S
成纤维细胞是胃癌间质中最常见的细胞。这些特化的成纤维细胞提供影响肿瘤行为的信号因子。在这里，我们发现这些与癌症相关的成纤维细胞为胃癌提供了信号蛋白Wnt5A及其受体ROR2。我们进一步证明，转移的受体ROR2在肿瘤细胞中仍然活跃，从而影响细胞的极化和迁移。我们的发现表明，我们对肿瘤中信号成分是如何运输的有了新的机制理解；因此，我们的发现增加了癌症间质在影响侵袭和转移方面的额外作用。肿瘤相关成纤维细胞(CAF)是肿瘤微环境中影响肿瘤进展的重要成分。除了形成细胞外基质外，这些成纤维细胞还提供信号因子来促进肿瘤存活和改变肿瘤行为。在胃癌中，影响侵袭和转移的一个重要信号通路是Wnt/Planar Cell Polity(PCP)信号。在这种情况下，关键的PCP配体是Wnt5A，它是由CAF产生的，胃癌细胞通过增强极化迁移对这一信号做出反应。为什么胃癌细胞对这一信号做出反应仍不清楚，因为它们对中心Wnt5A受体ROR2的表达水平非常低。在这里，我们显示CAF显示长的分支丝状足细胞，形成一个广泛的、复杂的网络吞噬胃癌细胞，例如胃癌细胞系AGS。CAF中ROR2的表达水平明显高于正常胃成纤维细胞和AGS细胞。通过高分辨率成像，我们观察到荧光标记的ROR2通过丝状伪足信号直接从CAF转移到AGS细胞，称为细胞素。令人惊讶的是，我们发现转移的ROR2复合体可以激活AGS细胞中的Wnt/JNK信号。一直以来，阻断CAF中的ROR2功能会导致旁分泌Wnt/JNK信号、细胞极化和接收AGS细胞的迁移减少。在斑马鱼体内模型中，观察到通过旁分泌ROR2转移来补充、增强迁移。这些发现证明了细胞线介导的信号在肿瘤微环境中的新作用。细胞素将Wnt受体从CAF传递到胃癌细胞，使它们能够对Wnt/PCP信号做出反应。
Fibroblasts are the prevalent cells in the stroma of gastric carcinoma. These specialized fibroblasts provide signaling factors influencing tumor behavior. Here, we show that these cancer-associated fibroblasts provide both the signaling protein WNT5A and its receptor ROR2 to gastric cancer. We further demonstrate that the transferred receptor ROR2 remains active in the tumor cells to influence cell polarization and migration. Our findings suggest a fresh mechanistic understanding of how signaling components are conveyed in a tumor; thus, our findings add an additional role of the cancer stroma in influencing invasion and metastasis. Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment influencing cancer progression. Besides shaping the extracellular matrix, these fibroblasts provide signaling factors to facilitate tumor survival and alter tumor behavior. In gastric cancer, one crucial signaling pathway influencing invasion and metastasis is the Wnt/Planar Cell Polarity (PCP) signaling. The crucial PCP ligand in this context is WNT5A, which is produced by the CAFs, and gastric cancer cells react upon this signal by enhanced polarized migration. Why gastric cancer cells respond to this signal is still unclear, as their expression level for the central WNT5A receptor, ROR2, is very low. Here, we show that CAFs display long and branched filopodia that form an extensive, complex network engulfing gastric cancer cells, such as the gastric cancer cell line AGS. CAFs have a significantly higher expression level of ROR2 than normal gastric fibroblasts and AGS cells. By high-resolution imaging, we observe a direct transfer of fluorescently tagged ROR2 from CAF to AGS cells by signaling filopodia, known as cytonemes. Surprisingly, we find that the transferred ROR2 complexes can activate Wnt/JNK signaling in AGS cells. Consistently, blockage of ROR2 function in the CAFs leads to reduced paracrine Wnt/JNK signaling, cell polarization, and migration of the receiving AGS cells. Complementary, enhanced migration via paracrine ROR2 transfer was observed in a zebrafish in vivo model. These findings demonstrate a fresh role for cytoneme-mediated signaling in the tumor microenvironment. Cytonemes convey Wnt receptors from CAFs to gastric cancer cells, allowing them to respond to Wnt/PCP signals.
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影响因子：
2.1
作者：
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通讯作者：
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