TGF-β1-based restoration of sodium iodide symporter expression in radioiodine-refractory differentiated thyroid cancer via engineered MSCs
The sodium iodide symporter (NIS) mediates iodide uptake into thyroid follicular cells, providing the basis for radioiodine (RAI) imaging and therapy of differentiated thyroid cancer (DTC). Loss of functional NIS expression leads to RAI-refractory disease. Restoration of RAI uptake via NIS delivery into tumors using mesenchymal stem cells (MSCs) represents a therapeutic strategy for RAI-refractory DTC. This study exploits transforming growth factor β (TGF-β) biology in RAI-refractory BRAF<sup>V600E</sup>-mutant papillary thyroid cancer (PTC) to selectively drive NIS transgene expression in engineered MSCs using a synthetic TGF-β1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) to reestablish RAI accumulation. The <sup>125</sup>I uptake assay confirmed stimulation of functional NIS expression in SMAD-NIS-MSCs through TGF-β1 released from BRAF<sup>V600E</sup>-mutant PTC cell lines (BCPAP, K1) from co-culture or by incubation with tumor-conditioned medium. Chemotaxis assays showed directed chemotaxis of MSCs toward BCPAP- and K1-tumor-conditioned medium. SMAD-NIS-MSCs applied intravenously to mice harboring BCPAP or K1 xenografts followed by <sup>123</sup>I scintigraphy demonstrated tumor-specific MSC recruitment and RAI accumulation. Application of SMAD-NIS-MSCs followed by <sup>131</sup>I demonstrated a significant delay in tumor growth with prolonged survival. We demonstrate re-establishment of NIS-mediated RAI therapy in RAI-refractory BRAF<sup>V600E</sup>-mutant PTC tumors using MSC-mediated NIS gene delivery driven by their TGF-β1 biology.
Authors
- Katja Steiger (ORCID: https://orcid.org/0000-0002-7269-5433)
- Peter J. Nelson (ORCID: https://orcid.org/0000-0002-2434-740X)
- Peter Bartenstein
- Christina Stauss (ORCID: https://orcid.org/0000-0002-2334-2949)
- Carolin Kitzberger (ORCID: https://orcid.org/0000-0002-6710-5873)
- Rebekka Spellerberg (ORCID: https://orcid.org/0000-0002-6837-9104)
- Joerg Kumbrink
- Nathalie Schwenk
- Christian Zach (ORCID: https://orcid.org/0000-0003-4986-0485)
- Kathrin A. Schmohl (ORCID: https://orcid.org/0000-0001-8792-6401)
- John C. Morris (ORCID: https://orcid.org/0000-0001-9820-5618)
- Christine Spitzweg (ORCID: https://orcid.org/0000-0002-0413-9697)
- Viktoria Florentine Koehler (ORCID: https://orcid.org/0000-0002-2665-1181)
- Wolfgang Weber (ORCID: https://orcid.org/0000-0002-7854-4345)
- Han Yang (ORCID: https://orcid.org/0000-0001-8994-7804)
- Sibylle Ziegler (ORCID: https://orcid.org/0000-0002-5321-4817)
- James Nagarajah (ORCID: https://orcid.org/0000-0002-3555-0809)
Institutions
- Radboud University Nijmegen (NL)
- TUM Klinikum (DE)
- Radboud University Medical Center (NL)
- LMU Klinikum (DE)
- Düsseldorf University Hospital (DE)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
- Heinrich Heine University Düsseldorf (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2025-10-18
- DOI
- https://doi.org/10.1016/j.ymthe.2025.10.033
- Primary Topic
- Thyroid Cancer Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wilhelm Sander-Stiftung
- Deutsche Forschungsgemeinschaft
- Technische Universität München
- Ludwig-Maximilians-Universität München
- Deutsche Krebshilfe