Recapitulating thyroid cancer histotypes through engineering embryonic stem cells

Veronica Veschi, Alice Turdo, Chiara Modica, Francesco Verona, Simone Franco, Miriam Gaggianesi, Elena Tirrò, Sebastiano 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 and Giorgio Stassi ()
Additional contact information
Veronica Veschi: University of Palermo
Alice Turdo: University of Palermo
Chiara Modica: University of Palermo
Francesco Verona: University of Palermo
Simone Franco: University of Palermo
Miriam Gaggianesi: University of Palermo
Elena Tirrò: University of Palermo
Sebastiano Bella: University of Palermo
Melania Lo Iacono: University of Palermo
Vincenzo Davide Pantina: University of Palermo
Gaetana Porcelli: University of Palermo
Laura Rosa Mangiapane: University of Palermo
Paola Bianca: University of Palermo
Aroldo Rizzo: Villa Sofia-Cervello Hospital
Elisabetta Sciacca: Queen Mary University, Experimental Medicine & Rheumatology
Irene Pillitteri: University of Palermo
Veronica Vella: University of Catania, Garibaldi-Nesima Hospital
Antonino Belfiore: University of Catania, Garibaldi-Nesima Hospital
Maria Rita Bongiorno: University of Palermo
Giuseppe Pistone: University of Palermo
Lorenzo Memeo: Mediterranean Institute of Oncology, Viagrande
Lorenzo Colarossi: Mediterranean Institute of Oncology, Viagrande
Dario Giuffrida: Mediterranean Institute of Oncology, Viagrande
Cristina Colarossi: Mediterranean Institute of Oncology, Viagrande
Paolo Vigneri: University of Catania
Matilde Todaro: University of Palermo
Giorgio Stassi: University of Palermo

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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 BRAFV600E or NRASQ61R mutations generate papillary or follicular TC, respectively, whereas addition of TP53R248Q 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36922-1

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DOI: 10.1038/s41467-023-36922-1

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