title: Platelet derived growth factor receptor alpha mediates nodal metastases in papillary thyroid cancer by driving the epithelial-mesenchymal transition.
abstract: Recently platelet derived growth factor receptor-alpha (PDGFRα) was recognized as a potential target to treat aggressive papillary thyroid cancer given its strong association with lymph node metastases. However, it is unclear how PDGFRα potentiates metastases and if it works through the canonical MAPK pathway traditionally linked to PTC oncogenesis. We explored the phenotypic changes driven by PDGFRα activation in human papillary thyroid cancer (PTC) cells and the downstream signalling cascades through which they are effected. We demonstrate that PDGFRα drives an impressive phenotypic change in PTC cell lines as documented by significant cytoskeletal rearrangement, increased migratory potential, and the formation of invadopodia. Cells lacking PDGFRα formed compact and dense spheroids, whereas cells expressing active PDGFRα exhibited invadopodia in three-dimensional culture. To achieve this, active PDGFRα provoked downstream activation of the MAPK/Erk, PI3K/Akt and STAT3 pathways. We further confirmed the role of PDGFRα as a transformative agent promoting the epithelial to mesenchymal transition of PTC cells, through the augmentation of Snail and Slug expression. Crenolanib, a small molecule inhibitor of PDGFRα, suppressed the levels of Snail and Slug and almost completely reversed all the phenotypic changes. We demonstrate that PDGFRα activation is an essential component that drives aggressiveness in PTC cells, and that the signaling pathways are complex, involving not only the MAPK/Erk but also the PI3K/Akt and STAT3 pathways. This argues for upstream targeting of the PDGFRα given the redundancy of oncogenic pathways in PTC, especially in patients whose tumors over-express this tyrosine kinase receptor.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Canada.
authors.forename: Esther
authors.initials: E
authors.lastname: Ekpe-Adewuyi
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Lopez-Campistrous
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Canada.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Canada.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Canada.|Division of Surgical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada.
authors.forename: Todd P W
authors.initials: TP
authors.lastname: McMullen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D000069261:Podosomes / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D010880:Piperidines; C000604407:SNAI1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071250:Snail Family Transcription Factors; D058539:Phosphatidylinositol 3-Kinase; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C577197:crenolanib
keywords: crenolanib; epithelial to mesenchymal transition (EMT); invadopodia; papillary thyroid cancer (PTC); platelet derived growth factor receptor-alpha (PDGFRα)