Molecular therapy : the journal of the American Society of Gene TherapyOct 19, 2025

Using modified stem cells with TGF-β1 to restore iodine intake protein in thyroid cancer resistant to radioiodine treatment

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

Restoration of radioiodine uptake in RAI-refractory BRAF-mutant thyroid cancer was achieved through engineered stem cells that express the sodium iodide symporter.

Loss of functional sodium iodide symporter (NIS) expression is associated with radioiodine-refractory disease in differentiated thyroid cancer.
Mesenchymal stem cells (MSCs) can be engineered to deliver NIS to tumors as a potential therapeutic strategy.
The study utilized a synthetic promoter that responds to transforming growth factor β (TGF-β1) to drive NIS expression in MSCs.
Functional NIS expression was stimulated in MSCs through TGF-β1 from BRAF-mutant papillary thyroid cancer cell lines.
Directed movement of MSCs toward tumor-conditioned medium was observed, indicating tumor-specific recruitment.
Application of engineered MSCs in mice led to significant tumor growth delay and prolonged survival.

Simplified

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-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. TheI uptake assay confirmed stimulation of functional NIS expression in SMAD-NIS-MSCs through TGF-β1 released from BRAF-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 byI scintigraphy demonstrated tumor-specific MSC recruitment and RAI accumulation. Application of SMAD-NIS-MSCs followed byI demonstrated a significant delay in tumor growth with prolonged survival. We demonstrate re-establishment of NIS-mediated RAI therapy in RAI-refractory BRAF-mutant PTC tumors using MSC-mediated NIS gene delivery driven by their TGF-β1 biology. V600E125V600E123 131V600E

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Using modified stem cells with TGF-β1 to restore iodine intake protein in thyroid cancer resistant to radioiodine treatment

Abstract

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