PDGFRα Regulates Follicular Cell Differentiation Driving Treatment Resistance and Disease Recurrence in Papillary Thyroid Cancer

EBioMedicine. 2016 Oct;12:86-97. doi: 10.1016/j.ebiom.2016.09.007. Epub 2016 Sep 10.

Abstract

Dedifferentiation of follicular cells is a central event in resistance to radioactive iodine and patient mortality in papillary thyroid carcinoma (PTC). We reveal that platelet derived growth factor receptor alpha (PDGFRα) specifically drives dedifferentiation in PTC by disrupting the transcriptional activity of thyroid transcription factor-1 (TTF1). PDGFRα activation dephosphorylates TTF1 consequently shifting the localization of this transcription factor from the nucleus to the cytoplasm. TTF1 is required for follicular cell development and disrupting its function abrogates thyroglobulin production and sodium iodide transport. PDGFRα also promotes a more invasive and migratory cell phenotype with a dramatic increase in xenograft tumor formation. In patient tumors we confirm that nuclear TTF1 expression is inversely proportional to PDGFRα levels. Patients exhibiting PDGFRα at time of diagnosis are three times more likely to exhibit nodal metastases and are 18 times more likely to recur within 5years than those patients lacking PDGFRα expression. Moreover, high levels of PDGFRα and low levels of nuclear TTF1 predict resistance to radioactive iodine therapy. We demonstrate in SCID xenografts that focused PDGFRα blockade restores iodide transport and decreases tumor burden by >50%. Focused PDGFRα inhibitors, combined with radioactive iodine, represent an additional avenue for treating patients with aggressive variants of PTC.

Keywords: Metastases; Papillary thyroid cancer; Platelet derived growth factor receptor; TTF1(Nkx2-1).

MeSH terms

  • Animals
  • Biological Transport
  • Carcinoma / drug therapy
  • Carcinoma / genetics*
  • Carcinoma / mortality
  • Carcinoma / pathology*
  • Carcinoma, Papillary
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Nucleus / metabolism
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, SCID
  • Models, Biological
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local
  • Phenotype
  • Prognosis
  • Protein Transport
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Sodium Iodide / metabolism
  • Thyroglobulin / biosynthesis
  • Thyroid Cancer, Papillary
  • Thyroid Epithelial Cells / metabolism*
  • Thyroid Epithelial Cells / pathology*
  • Thyroid Neoplasms / drug therapy
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / mortality
  • Thyroid Neoplasms / pathology*
  • Transcription Factors
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • TTF1 protein, human
  • Transcription Factors
  • Thyroglobulin
  • Receptor, Platelet-Derived Growth Factor alpha
  • Sodium Iodide