PDGFRα Regulates Follicular Cell Differentiation Driving Treatment Resistance and Disease Recurrence in Papillary Thyroid Cancer.
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.
Department of Surgery, University of Alberta, Edmonton, Canada.
Ana
A
Lopez-Campistrous
Department of Surgery, University of Alberta, Edmonton, Canada.
Esther Ekpe
EE
Adewuyi
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Matthew G K
MGK
Benesch
Department of Surgery, University of Alberta, Edmonton, Canada.
Yi Man
YM
Ko
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
Raymond
R
Lai
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
Aducio
A
Thiesen
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Jay
J
Dewald
Department of Internal Medicine, University of Alberta, Edmonton, Canada.
Peng
P
Wang
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Karen
K
Chu
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Sunita
S
Ghosh
Department of Surgery, University of Alberta, Edmonton, Canada.
David C
DC
Williams
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Larissa J
LJ
Vos
Department of Biochemistry, University of Alberta, Edmonton, Canada.
David N
DN
Brindley
Department of Surgery, University of Alberta, Edmonton, Canada; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada. Electronic address: todd.mcmullen@ualberta.ca.
Todd P W
TPW
McMullen
D000818:Animals; D001692:Biological Transport; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D011379:Prognosis; D021381:Protein Transport; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D012974:Sodium Iodide / Q000378:metabolism; D013954:Thyroglobulin / Q000096:biosynthesis; D000077273:Thyroid Cancer, Papillary; D000072637:Thyroid Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D014157:Transcription Factors; D023041:Xenograft Model Antitumor Assays
D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; D013954:Thyroglobulin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D012974:Sodium Iodide
Metastases; Papillary thyroid cancer; Platelet derived growth factor receptor; TTF1(Nkx2-1)
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