Department of Surgical Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
Department of Health Promotion Sciences, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
Nat Commun. 2023 Mar 11;14(1):1351. doi: 10.1038/s41467-023-36922-1.
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 or NRAS mutations generate papillary or follicular TC, respectively, whereas addition of TP53 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.
甲状腺癌（TC）是内分泌器官最常见的恶性肿瘤。不同 TC 组织类型的起源细胞亚群在细胞谱系层次结构中尚不清楚。经过适当的体外刺激，人类胚胎干细胞（hESC）会逐步分化为甲状腺祖细胞（TPCs-第 22 天），然后成熟为甲状腺细胞（第 30 天）。在这里，我们通过 CRISPR-Cas9 在 hESC 衍生的 TPC 中递送特定的基因组改变，创建了所有不同组织类型的滤泡细胞衍生的 TC。具体来说，携带 BRAF 或 NRAS 突变的 TPC 分别产生乳头状或滤泡状 TC，而添加 TP53 则会产生未分化的 TC。值得注意的是，TC 是通过工程化 TPC 产生的，而成熟的甲状腺细胞具有非常有限的致瘤能力。当在早期分化的 hESC 中递送相同的突变时，会导致畸胎瘤。组织抑制剂金属蛋白酶 1（TIMP1）/基质金属蛋白酶 9（MMP9）/分化簇 44（CD44）三元复合物与 Kisspeptin 受体（KISS1R）合作，参与 TC 的发生和进展。增加放射性碘摄取、针对 KISS1R 和 TIMP1 的靶向治疗可能是未分化 TC 的一种治疗辅助选择。
