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.
Authors
- Mayu Shigeyama
- Akira Hara (ORCID: https://orcid.org/0000-0002-5554-8060)
- Hiroyuki Tomita (ORCID: https://orcid.org/0000-0002-3291-0274)
- Koki Kato (ORCID: https://orcid.org/0000-0003-2562-1893)
- Tomoya Hirata (ORCID: https://orcid.org/0000-0002-4533-1343)
- Haruhiko Akiyama (ORCID: https://orcid.org/0000-0002-5661-9895)
- Naoki Nishio (ORCID: https://orcid.org/0000-0003-1495-0376)
- Akari Unome
- Shingo Komura (ORCID: https://orcid.org/0000-0002-7639-7484)
- Masashi Kuroki (ORCID: https://orcid.org/0000-0002-3199-009X)
- Takenori Ogawa (ORCID: https://orcid.org/0000-0003-1556-7328)
- Hirofumi Shibata (ORCID: https://orcid.org/0000-0002-7104-9456)
- Ryo Ishii (ORCID: https://orcid.org/0000-0001-5946-8626)
- Shin Tsunekawa (ORCID: https://orcid.org/0000-0002-9890-5777)
- Ryo Kawaura (ORCID: https://orcid.org/0000-0002-8993-1834)
- Shioko Kimura (ORCID: https://orcid.org/0000-0001-9627-6818)
- Hiromasa Ishihara
- Shigeo Takashima
- Yasuhiro Yamada
Institutions
- National Institutes of Health (US)
- Mie University (JP)
- Tohoku University (JP)
- National Cancer Institute (US)
- Gifu University (JP)
- Center for One Medicine Innovative Translational Research (JP)
- Gifu University Institute for Advanced Study (JP)
- Nagoya University (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-10-26
- DOI
- https://doi.org/10.1016/j.celrep.2026.118195
- Primary Topic
- Thyroid Cancer Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency