Embryonic reprogramming drives anaplastic transformation in thyroid carcinoma

Abstract

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.

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BibTeX RIS

BibTeX

@article{kawaura2026embryonic,
  title = {{Embryonic reprogramming drives anaplastic transformation in thyroid carcinoma}},
  author = {Ryo Kawaura and Akari Unome and Hiroyuki Tomita and Hiromasa Ishihara and Masashi Kuroki and Shingo Komura and Koki Kato and Shigeo Takashima and Naoki Nishio and Mayu Shigeyama and Tomoya Hirata and Ryo Ishii and Shioko Kimura and Shin Tsunekawa and Haruhiko Akiyama and Akira Hara and Yasuhiro Yamada and Takenori Ogawa and Hirofumi Shibata},
  journal = {Cell Reports},
  year = {2026},
  month = oct,
  doi = {10.1016/j.celrep.2026.118195},
  url = {https://linkinghub.elsevier.com/retrieve/pii/S221112472601274X},
  note = {CC BY-NC 4.0},
}

RIS

TY  - JOUR
TI  - Embryonic reprogramming drives anaplastic transformation in thyroid carcinoma
AU  - Ryo Kawaura
AU  - Akari Unome
AU  - Hiroyuki Tomita
AU  - Hiromasa Ishihara
AU  - Masashi Kuroki
AU  - Shingo Komura
AU  - Koki Kato
AU  - Shigeo Takashima
AU  - Naoki Nishio
AU  - Mayu Shigeyama
AU  - Tomoya Hirata
AU  - Ryo Ishii
AU  - Shioko Kimura
AU  - Shin Tsunekawa
AU  - Haruhiko Akiyama
AU  - Akira Hara
AU  - Yasuhiro Yamada
AU  - Takenori Ogawa
AU  - Hirofumi Shibata
PY  - 2026
DA  - 2026/10/30
JO  - Cell Reports
DO  - 10.1016/j.celrep.2026.118195
UR  - https://linkinghub.elsevier.com/retrieve/pii/S221112472601274X
AB  - 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.
SN  - 2211-1247
ER  -

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