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 BRAFV600E-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 125I uptake assay confirmed stimulation of functional NIS expression in SMAD-NIS-MSCs through TGF-β1 released from BRAFV600E-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 123I scintigraphy demonstrated tumor-specific MSC recruitment and RAI accumulation. Application of SMAD-NIS-MSCs followed by 131I demonstrated a significant delay in tumor growth with prolonged survival. We demonstrate re-establishment of NIS-mediated RAI therapy in RAI-refractory BRAFV600E-mutant PTC tumors using MSC-mediated NIS gene delivery driven by their TGF-β1 biology.