Interaction between Ras and Src clones causes interdependent tumor malignancy via Notch signaling in Drosophila
Interaction between Ras and Src clones causes interdependent tumor malignancy via Notch signaling in Drosophila
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DOI：
10.1016/j.devcel.2021.07.002
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发表时间：
2021-08-09
影响因子：
11.8
通讯作者：
Igaki，Tatsushi
中科院分区：
文献类型：
--
作者：
Enomoto，Masato;Takemoto，Daisaku;Igaki，Tatsushi
癌症组织通常由多个肿瘤克隆组成，这些肿瘤克隆具有不同的致癌改变，如Ras或Src活化，但肿瘤异质性驱动癌症进展的机制仍然难以捉摸。在果蝇想象上皮中，Ras或src激活的良性肿瘤克隆相互作用，相互促进肿瘤恶性。在机制上，ras激活的细胞上调细胞表面配体Delta，而Src激活的细胞上调其受体Notch，导致Src细胞中Notch激活。Notch信号升高可诱导转录抑制因子Zfh1/ZEB1下调e -钙粘附蛋白和细胞死亡基因，导致src激活的侵袭性肿瘤。同时，Src细胞中的Notch激活上调细胞因子Unpaired/IL-6，从而激活邻近Ras细胞中的JAK-STAT信号。升高的JAK-STAT信号上调btb -锌指蛋白Chinmo，其下调e -钙粘连蛋白，从而产生ras激活的侵袭性肿瘤。我们的研究结果为肿瘤异质性如何通过细胞间相互作用引发肿瘤进展提供了机制解释。
Cancer tissue often comprises multiple tumor clones with distinct oncogenic alterations such as Ras or Src activation, yet the mechanism by which tumor heterogeneity drives cancer progression remains elusive. Here, we show inDrosophilaimaginal epithelium that clones of Ras- or Src-activated benign tumors interact with each other to mutually promote tumor malignancy. Mechanistically, Ras-activated cells upregulate the cell-surface ligand Delta while Src-activated cells upregulate its receptor Notch, leading to Notch activation in Src cells. Elevated Notch signaling induces the transcriptional repressor Zfh1/ZEB1, which downregulatesE-cadherinand cell death genehid, leading to Src-activated invasive tumors. Simultaneously, Notch activation in Src cells upregulates the cytokine Unpaired/IL-6, which activates JAK-STAT signaling in neighboring Ras cells. Elevated JAK-STAT signaling upregulates the BTB-zinc-finger protein Chinmo, which downregulatesE-cadherinand thus generates Ras-activated invasive tumors. Our findings provide a mechanistic explanation for how tumor heterogeneity triggers tumor progression via cell-cell interactions.