School of Biomedical Sciences, Queensland University of Technology (QUT) located at the Translational Research Institute, Woolloongabba, Brisbane, QLD 4102, Australia
The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD 4102, Australia.
J Cell Sci. 2018 Aug 10;131(15):jcs213678. doi: 10.1242/jcs.213678.
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that control a diverse range of biological processes during development and in adult tissues. We recently reported that somatic FGFR2 mutations are associated with shorter survival in endometrial cancer. However, little is known about how these FGFR2 mutations contribute to endometrial cancer metastasis. Here, we report that expression of the activating mutations FGFR2 and FGFR2 in an endometrial cancer cell model induce Golgi fragmentation, and loss of polarity and directional migration. In mutant FGFR2-expressing cells, this was associated with an inability to polarise intracellular pools of FGFR2 towards the front of migrating cells. Such polarization defects were exacerbated in three-dimensional culture, where FGFR2 mutant cells were unable to form well-organised acini, instead undergoing exogenous ligand-independent invasion. Our findings uncover collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to poor outcome in endometrial cancer patients.
成纤维细胞生长因子受体（FGFRs）是受体酪氨酸激酶家族的一员，在发育过程中和成人组织中控制着多种生物学过程。我们最近报道称，体细胞 FGFR2 突变与子宫内膜癌患者的生存率降低有关。然而，这些 FGFR2 突变如何促进子宫内膜癌转移的机制尚不清楚。在这里，我们报告称，在子宫内膜癌细胞模型中表达激活突变的 FGFR2 和 FGFR2 会诱导高尔基体碎片化，并导致极性和定向迁移丧失。在表达突变 FGFR2 的细胞中，这与无法将细胞内 FGFR2 池极化到迁移细胞的前缘有关。在三维培养中，这种极化缺陷更加严重，突变型 FGFR2 细胞无法形成组织良好的腺泡，而是经历外源性配体非依赖性侵袭。我们的研究结果揭示了细胞集体极性和侵袭是与疾病相关的 FGFR2 突变的共同靶点，这些突变导致子宫内膜癌患者预后不良。
