FGFR2-activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer cell
Samantha J Stehbens1,2, Robert J Ju3,2, Mark N Adams3
1School of Biomedical Sciences, Queensland University of Technology (QUT) located at the Translational Research Institute, Woolloongabba, Brisbane, QLD 4102, Australia s.stehbens@uq.edu.au pamela.pollock@qut.edu.au.
Abstract:
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 FGFR2N550K and FGFR2Y376C 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.
Insights
Activating mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) disrupt cell polarity and migration, driving endometrial cancer metastasis. These FGFR2 mutations lead to invasion and poor patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases crucial for development and adult tissue homeostasis.
- Somatic mutations in FGFR2 are linked to reduced survival in endometrial cancer patients.
- The precise mechanisms by which FGFR2 mutations drive endometrial cancer metastasis remain largely unexplored.
Purpose of the Study:
- To investigate the functional consequences of activating FGFR2 mutations (FGFR2N550K and FGFR2Y376C) in endometrial cancer.
- To elucidate how these mutations impact cell polarity, migration, and invasion.
- To identify potential therapeutic targets for FGFR2-driven endometrial cancer.
Main Methods:
- Expression of activating FGFR2 mutations in an endometrial cancer cell model.
- Assessment of Golgi fragmentation, cell polarity, and directional migration.
- Analysis of FGFR2 intracellular localization during cell migration.
- Three-dimensional cell culture to evaluate acini formation and invasion.
Main Results:
- Expression of FGFR2N550K and FGFR2Y376C induced Golgi fragmentation and loss of cell polarity.
- Mutant FGFR2-expressing cells exhibited impaired directional migration due to failed polarization of FGFR2.
- In 3D cultures, mutant FGFR2 cells displayed defective acini formation and ligand-independent invasion.
Conclusions:
- Activating FGFR2 mutations disrupt collective cell polarity and promote invasion in endometrial cancer.
- These molecular defects are associated with poor clinical outcomes in endometrial cancer patients.
- Targeting cell polarity and invasion pathways may offer therapeutic strategies for FGFR2-mutated endometrial cancer.
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