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

EBioMedicine

Matthew G.K. Benesch¹  David N. Brindley¹  Jay Dewald¹  Peng Wang²  Aducio Thiesen³  Raymond Lai³  Karen Chu⁴  Larissa J. Vos⁴  Sunita Ghosh⁴  Yi Man Ko⁵  David C. Williams⁵  Ana Lopez-Campistrous⁵  Todd P.W. McMullen⁵  Esther Ekpe Adewuyi⁵ 

[1]Department of Biochemistry, University of Alberta, Edmonton, Canada

[2]Department of Internal Medicine, University of Alberta, Edmonton, Canada

[3]Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada

[4]Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

[5]Department of Surgery, University of Alberta, Edmonton, Canada

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

DOI  :  10.1016/j.ebiom.2016.09.007

来源: DOAJ

【 摘 要 】

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 5 years 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.

【 授权许可】

Unknown