Cytoneme-mediated signaling essential for tumorigenesis
Cytoneme-mediated signaling essential for tumorigenesis
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DOI：
10.1371/journal.pgen.1008415
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发表时间：
2019-09-01
期刊：
影响因子：
4.5
通讯作者：
Kornberg, Thomas B.
中科院分区：
文献类型：
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作者：
Fereres, Sol;Hatori, Ryo;Kornberg, Thomas B.
作者总结说，许多类型的肿瘤的生长依赖于与间质和非肿瘤邻居的生产性相互作用，尽管有证据表明肿瘤和间质细胞交换信号蛋白和它们产生的生长因子，但这些蛋白在信号细胞之间移动的机制尚未被研究，也不清楚。我们以前的工作表明，正常细胞在专门的丝状足细胞与信号伙伴接触的部位产生瞬时化学突触，在这项工作中，我们探索了肿瘤使用相同的机制与基质细胞沟通的可能性。我们发现细胞素介导的信号对于果蝇肿瘤的生长是必不可少的，果蝇肿瘤是人类EGFR过度表达和RET驱动的疾病的模型。值得注意的是，抑制细胞素可以治愈果蝇的致命肿瘤。肿瘤细胞与其微环境中的细胞之间的沟通对癌症的进展至关重要。为了研究细胞线介导的信号作为一种在肿瘤和肿瘤相关细胞之间分配生长因子信号蛋白的机制的作用，我们分析了EGFR和RET果蝇肿瘤模型，并测试了几种损害细胞线介导的信号的遗传功能丧失情况。神经胶质、反复无常、irk2、疤痕和透明是细胞素在正常发育过程中所需要的基因。神经胶质细胞和反复无常是细胞黏附蛋白，Irk2是钾通道，SCAR和Diaphanous是肌动蛋白结合蛋白，它们共同参与的唯一过程是细胞素介导的信号转导。我们观察到，这些基因中任何一个的功能减弱都抑制了肿瘤的生长，提高了机体的存活率。我们还注意到，表达EGFR的肿瘤圆盘有异常广泛的气管(呼吸管)和异位表达的无分支(BNL，一种成纤维细胞生长因子)和FGFR。BNL是一种已知的气管诱导因子，在其他环境中通过细胞素介导的过程发出信号，我们确定外源过表达显性负FGFR抑制了肿瘤的生长。我们的结果与细胞素在肿瘤和间质细胞之间移动信号蛋白的想法是一致的，并且细胞素介导的信号是肿瘤生长和恶性肿瘤所必需的。
Author summary The growth of many types of tumors depend on productive interactions with stromal, non-tumor neighbors, and although there is evidence that tumor and stromal cells exchange signaling proteins and growth factors that they produce, the mechanism by which these proteins move between the signaling cells has not been investigated and is not known. Our previous work has shown that normal cells make transient chemical synapses at sites where specialized filopodia called cytonemes contact signaling partners, and in this work we explore the possibility that tumors use the same mechanism to communicate with stromal cells. We show that cytoneme-mediated signaling is essential for growth of Drosophila tumors that model human EGFR over-expression and RET-driven disease. Remarkably, inhibition of cytonemes cures flies of lethal tumors.Communication between neoplastic cells and cells of their microenvironment is critical to cancer progression. To investigate the role of cytoneme-mediated signaling as a mechanism for distributing growth factor signaling proteins between tumor and tumor-associated cells, we analyzed EGFR and RET Drosophila tumor models and tested several genetic loss-of-function conditions that impair cytoneme-mediated signaling. Neuroglian, capricious, Irk2, SCAR, and diaphanous are genes that cytonemes require during normal development. Neuroglian and Capricious are cell adhesion proteins, Irk2 is a potassium channel, and SCAR and Diaphanous are actin-binding proteins, and the only process to which they are known to contribute jointly is cytoneme-mediated signaling. We observed that diminished function of any one of these genes suppressed tumor growth and increased organism survival. We also noted that EGFR-expressing tumor discs have abnormally extensive tracheation (respiratory tubes) and ectopically express Branchless (Bnl, a FGF) and FGFR. Bnl is a known inducer of tracheation that signals by a cytoneme-mediated process in other contexts, and we determined that exogenous over-expression of dominant negative FGFR suppressed and tumor growth. Our results are consistent with the idea that cytonemes move signaling proteins between tumor and stromal cells and that cytoneme-mediated signaling is required for tumor growth and malignancy.