Fibroblast Growth Factor Receptor 2 Activating Mutations Potentiate Migration and Invasion in Endometrial Cancer — ASN Events
  1. Schedule
  2. Session 18: Cell Architecture and Mechanobiology
  3. Fibroblast Growth Factor Receptor 2 Activating Mutations Potentiate Migration and Invasion in Endometrial Cancer

Fibroblast Growth Factor Receptor 2 Activating Mutations Potentiate Migration and Invasion in Endometrial Cancer (#61)

Samantha Stehbens 1 2 , Robert Ju 1 , Mark Adams 1 , Pamela M Pollock 1
  1. Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
  2. Diamantina Institute, University of Queensland, Brisbane, QLD, Australia

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. FGFR2 shows pleiotrophy where multiple inherited syndromes are associated with different germline mutations affecting the ligand binding, juxtamembrane or kinase domain of the receptor. Our lab has identified somatic FGFR2 mutations in endometrial cancers (ECs) with ~90% of mutations occurring at one of six hotspot codons, some of which are associated with different syndromic phenotypes. We recently reported that FGFR2 mutations are associated with shorter progression-free survival and cancer specific survival in a cohort of over 950 EC patients. Little is known about how these different FGFR2 mutations may contribute to the metastatic spread of EC.

Here we report that following transduction of eGFP-tagged WT (FGFR2WT), or the activating mutations, FGFR2N550K and FGFR2Y376C, into Ishikawa endometrial cells, we observed aberrant localization of the mutant receptors to a perinuclear pool, in contrast to FGFR2WT which showed more membrane expression. This abberant intracellular localization pattern was concomitant with constitutive PLCγ signalling, Golgi fragmentation and a loss of front-rear cell polarity. Detailed two-dimensional migration studies showed cells expressing FGFR activating mutations exhibited a decrease in migrational persistence in both chemokinesis and chemotaxis assays.

Finally we have recapitulated the loss of polarity in a physiological three-dimensional environment, in which Ishikawa cells transduced with FGFR2N550K and FGFR2Y376C grew as irregular acini, lacking luminal structures and exhibiting fragmented Golgi. Furthermore, we observed differential acini morphologies in cells transduced with FGFR2N550K and FGFR2Y376C. We found that cells expressing FGFR2N550K exhibited a multi-lobular acini phenotype in which matrix invasion was potentiated with FGF10 ligand stimulation. In contrast, cells transduced with FGFR2Y376C, resulted in large dysmorphic acini with a lower invasion propensity, instead exhibiting a rapidly proliferating, bulging morpholology. Taken together, these findings highlight the need to study the molecular basis of different FGFR2 mutations to better understand how they differentially impact invasion and migration and thus contribute to the poor prognosis observed in patients.