Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
Curr Biol. 2014 Jul 7;24(13):1476-84. doi: 10.1016/j.cub.2014.05.043.
Cancers develop in a complex mutational landscape. Interaction of genetically abnormal cancer cells with normal stromal cells can modify the local microenvironment to promote disease progression for some tumor types. Genetic models of tumorigenesis provide the opportunity to explore how combinations of cancer driver mutations confer distinct properties on tumors. Previous Drosophila models of EGFR-driven cancer have focused on epithelial neoplasia.
Here, we report a Drosophila genetic model of EGFR-driven tumorigenesis in which the neoplastic transformation depends on interaction between epithelial and mesenchymal cells. We provide evidence that the secreted proteoglycan Perlecan can act as a context-dependent oncogene cooperating with EGFR to promote tumorigenesis. Coexpression of Perlecan in the EGFR-expressing epithelial cells potentiates endogenous Wg/Wnt and Dpp/BMP signals from the epithelial cells to support expansion of a mesenchymal compartment. Wg activity is required in the epithelial compartment, whereas Dpp activity is required in the mesenchymal compartment. This genetically normal mesenchymal compartment is required to support growth and neoplastic transformation of the genetically modified epithelial population.
We report a genetic model of tumor formation that depends on crosstalk between a genetically modified epithelial cell population and normal host mesenchymal cells. Tumorigenesis in this model co-opts a regulatory mechanism that is normally involved in controlling growth of the imaginal disc during development.
癌症是在复杂的突变景观中发展起来的。遗传异常的癌细胞与正常基质细胞的相互作用可以改变局部微环境，促进某些肿瘤类型的疾病进展。肿瘤发生的遗传模型为探索癌症驱动突变的组合如何赋予肿瘤不同的特性提供了机会。先前的 EGFR 驱动的癌症果蝇模型主要集中在上皮性肿瘤上。
在这里，我们报告了一个 EGFR 驱动的肿瘤发生的果蝇遗传模型，其中肿瘤的转化取决于上皮细胞和间充质细胞之间的相互作用。我们提供的证据表明，分泌型蛋白聚糖 Perlecan 可以作为一个与 EGFR 合作促进肿瘤发生的上下文相关的癌基因。Perlecan 在表达 EGFR 的上皮细胞中的共表达增强了来自上皮细胞的内源性 Wg/Wnt 和 Dpp/BMP 信号，以支持间充质细胞的扩增。Wg 活性在上皮细胞中是必需的，而 Dpp 活性在间充质细胞中是必需的。这种遗传上正常的间充质细胞群是支持遗传修饰的上皮细胞群体生长和肿瘤转化所必需的。
我们报告了一个依赖于遗传修饰的上皮细胞群体与正常宿主间充质细胞之间相互作用的肿瘤形成遗传模型。该模型中的肿瘤发生共同涉及到一个正常参与发育过程中 imaginal disc 生长的调控机制。
