Embryonic reprogramming drives anaplastic transformation in thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that often arises through anaplastic transformation of papillary thyroid carcinoma (PTC). Although genetic drivers such as BRAF and TP53 mutations are implicated, the mechanisms underlying this transition remain poorly understood. Here, we show that human ATC loses thyroid differentiation and acquires pluripotency-associated features, accompanied by MAPK pathway activation. Guided by parallels with induced pluripotent stem cell reprogramming, we develop an in vivo reprogramming mouse model. Forced expression of Oct3/4, Sox2, Klf4, and c-Myc (OSKM) induces anaplastic transformation of Braf-mutant thyroid epithelium even without Trp53 mutation, yielding an ATC-like phenotype that shares molecular and histological features with human ATC. A conventional Braf/Trp53-mutant model shows similar features. Reintroduction of NKX2-1 into human and murine ATC cells partially reverses embryonic reprogramming, suppresses proliferation and induces redifferentiation toward a PTC-like phenotype. Embryonic reprogramming is a central driver of anaplastic transformation and supports redifferentiation strategies.