Recapitulating thyroid cancer histotypes through engineering embryonic stem cells

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 vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create 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 addition of TP53 R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs.

Veronica Veschi, Alice Turdo, Chiara Modica, Francesco Verona, Simone Di Franco, Miriam Gaggianesi, Elena Tirrò, Sebastiano Di Bella, Melania Lo Iacono, Vincenzo Davide Pantina, Gaetana Porcelli, Laura Rosa Mangiapane, Paola Bianca, Aroldo Rizzo, Elisabetta Sciacca, Irene Pillitteri, Veronica Vella, Antonino Belfiore, Maria Rita Bongiorno, Giuseppe Pistone, Lorenzo Memeo, Lorenzo Colarossi, Dario Giuffrida, Cristina Colarossi, Paolo Vigneri, Matilde Todaro, Giorgio Stassi