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.
Highlights
The global incidence of thyroid cancer has risen steadily over the last 40 years and in many countries it is expected to surpass colorectal cancer to become the fourth leading cancer diagnosis by 2030 [1, 2]
The management of metastatic papillary thyroid cancer (PTC) is challenging because of significant morbidity as a result of repeated surgical resections or high-dose radioactive iodine treatments, which become the only recourse upon recurrence [5]
We demonstrate that specific blockade of PDGFRα is sufficient to reverse the aggressive phenotypic changes seen in PTC cells and this may represent an advance in therapy for those patients with progressive, metastatic disease
Summary
The global incidence of thyroid cancer has risen steadily over the last 40 years and in many countries it is expected to surpass colorectal cancer to become the fourth leading cancer diagnosis by 2030 [1, 2]. This increase is largely attributable to a tripling in the incidence of papillary thyroid cancer (PTC), which accounts for about 90% of thyroid cancers [1, 3]. Randomized clinical trials have examined a repertoire of kinase receptor inhibitors for their ability www.impactjournals.com/oncotarget to slow disease progression in patients failing surgical or radioactive iodine ablation treatment.
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