TERT accelerates BRAF mutant–induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis
Menée in vitro et à l'aide d'un modèle murin transgénique, cette étude met en évidence un mécanisme par lequel la transcriptase TERT, en stimulant l'expression de l'ARN ribosomal, induit la dédifférenciation des cellules cancéreuses de la thyroïde et favorise la progression tumorale
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. Evidence shows TERT induces thyroid cancer progression by promoting ribosomal biogenesis, with promising therapeutic implications.