TGF-β1-based restoration of sodium iodide symporter expression in radioiodine-refractory differentiated thyroid cancer via engineered MSCs

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The sodium iodide symporter (NIS) mediates iodine uptake into thyroid follicular cells providing the basis for radioiodine imaging and therapy of differentiated thyroid cancer. Loss of functional NIS expression leads to radioiodine-refractory disease. Restoration of radioiodine uptake via NIS delivery into tumors using mesenchymal stem cells (MSCs) represents a therapeutic strategy for radioiodine-refractory differentiated thyroid cancer. This study exploits transforming growth factor-beta (TGF-β) biology in radioiodine-refractory BRAF V600E -mutant papillary thyroid cancer to selectively drive NIS transgene expression in engineered MSCs using a synthetic TGF-β1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) to reestablish radioiodine accumulation. 125 I uptake assay confirmed stimulation of functional NIS expression in SMAD-NIS-MSCs through TGF-β1 released from BRAF V600E -mutant papillary thyroid cancer cell lines (BCPAP, K1) from co-culture or by incubation with tumor-conditioned medium. Chemotaxis assays showed directed chemotaxis of MSCs towards BCPAP- and K1-tumor-conditioned medium. SMAD-NIS-MSCs applied intravenously to mice harboring BCPAP or K1 xenografts followed by 123 I-scintigraphy demonstrated tumor-specific MSC recruitment and radioiodine accumulation. Application of SMAD-NIS-MSCs followed by 131 I demonstrated a significant delay in tumor growth with prolonged survival. We demonstrate re-establishment of NIS-mediated radioiodine therapy in radioiodine-refractory BRAF V600E -mutant papillary thyroid cancer tumors using MSC-mediated NIS gene delivery driven by their TGF-β1 biology.

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