Short Call Abstracts

Dedifferentiation of follicular cells is a central event in resistance to radioactive iodine and patient mortality in papillary thyroid carcinoma (PTC). We used six different thyroid cell lines, human primary cultures and SCID mouse xenograft models to explore how PDGFRa alters follicular cell differentiation as defined by TTF1, Pax8 expression and iodide transport. Confocal microscopy, invasion assays and 3D culture defined TTF1 subcellular targeting and cell phenotype. Immunohistochemistry on patient tissue arrays (n = 287) with matching clinical data (follow-up period 11 years) were used to map out recurrence rates as a function of PDGFRa and cytoplasmic TTF1 expression. We reveal that PDGFRa has a unique role in driving aggressive disease in PTC through a double-hit on follicular cells. First, PDGFRa specifically drives dedifferentiation by disrupting the transcriptional activity of TTF1. PDGFRa activation dephosphorylates TTF1 consequently shifting the localization of this transcription factor from the nucleus to the cytoplasm. Disrupted TTF1 function creates an invasive phenotype that lacks thyroglobulin production and sodium iodide symporter function. Patients exhibiting PDGFRa at time of diagnosis are three times more likely to exhibit nodal metastases and are 18 times more likely to recur within 5 years than those patients lacking PDGFRa expression. Moreover, high levels of PDGFRa and low levels of nuclear TTF1 predict resistance to radioactive iodine therapy. Secondly, PDGFRa transforms PTC cell lines as documented by cytoskeletal rearrangement, increased migratory potential, the formation of invadopodia and through the epithelial-mesenchymal transition by impressive augmentation of Snail and Slug expression. Crenolanib, a small molecule inhibitor of PDGFRa reverses these phenotypic changes. Moreover, we demonstrate in SCID xenografts that crenolanib treatment restores iodide transport and decreases tumor burden by more than 50%. We demonstrate that PDGFRa drives PTC metastases by disrupting TTF1 function and mediating the epithelial-mesenchymal transition. Focused inhibition of PDGFRa, combined with radioactive iodine, represents a new avenue for treating patients with aggressive variants of PTC.

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