2. Academic Validation
  3. TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis

TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis

  • Sci Adv. 2023 Sep;9(35):eadg7125. doi: 10.1126/sciadv.adg7125.
Pengcheng Yu 1 2 3 4,  Ning Qu 1 2,  Rui Zhu 3 4,  Jiaqian Hu 1 2,  Peizhen Han 1 2,  Jiahao Wu 1 2,  Licheng Tan 1 2,  Hualei Gan 2 5,  Cong He 1 2,  Chuantao Fang 3 4,  Yubin Lei 3 4,  Jian Li 3 4,  Chenxi He 4,  Fei Lan 4,  Xiao Shi 1 2,  Wenjun Wei 1 2,  Yu Wang 1 2,  Qinghai Ji 1 2,  Fa-Xing Yu 3 4,  Yu-Long Wang 1 2
Affiliations

Affiliations

  • 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China.
  • 4 Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
PMID: 37647391 DOI: 10.1126/sciadv.adg7125
Abstract

TERT reactivation occurs frequently in human malignancies, especially advanced cancers. However, in vivo functions of TERT reactivation in Cancer progression and the underlying mechanism are not fully understood. In this study, we expressed TERT and/or active BRaf (BRaf V600E) specifically in mouse thyroid epithelium. While BRaf V600E alone induced papillary thyroid Cancer (PTC), coexpression of BRaf V600E and TERT resulted in poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome analysis revealed that tumors from mice coexpressing BRaf V600E and TERT were highly heterogeneous, and cell dedifferentiation was positively correlated with ribosomal biogenesis. Mechanistically, TERT boosted ribosomal RNA (rRNA) expression and protein synthesis by interacting with multiple proteins involved in ribosomal biogenesis. Furthermore, we found that CX-5461, an rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation of thyroid Cancer. Thus, TERT promotes thyroid Cancer progression by inducing Cancer cell dedifferentiation, and ribosome inhibition represents a potential strategy to treat TERT-reactivated cancers.

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