Recapitulating thyroid cancer histotypes through engineering embryonic stem cells.. Homo sapiens

Thyroid carcinoma (TC) is the most common malignancy of endocrine organs.The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. Human embryonic stem cells (hESCs) with appropriate in vitrostimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day22), which maturate into thyrocytes (day 30). Here, we created follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically,TPCs harboring BRAF V600E or NRAS Q61R mutations generate papillary or follicular TC, respectively, whereas addiction of TP53 R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas engineered thyrocytes do not generate TCs. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. TIMP-1/MMP-9/CD44 ternary complex, in cooperation with KISS1R, is involved in TC initiation and progression.Increasing iodide uptake, KISS1R targeting may represent a therapeutic adjuvant option for undifferentiated TCs.