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

Abstract

AbstractTERT reactivation occurs frequently in human malignancies. While BRAF activating mutation widely existed in cancers at various stages, TERT reactivation mainly occurs in advanced tumors. However,in vivoevidence for TERT role in cancer progression and the underlying mechanism is currently lacking. In this study, we induced TERT and/or BRAF V600E expression in mouse thyroid epithelium. TERT overexpression alone had no evident effect on tumor initiation. BRAFVEexpression itself induced mediocre papillary thyroid cancer (PTC). Notably, the co-expression of BRAFVEand TERT resulted in aggressive poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome revealed that tumors from co-mutant mice were highly heterogeneous and dedifferentiation process significantly correlated with ribosomal pathways. Mechanistically, TERT boosted ribosomal RNA expression and protein synthesis. CX-5461, a rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation. Thus, TERT promotes thyroid cancer progression by inducing dedifferentiation, and ribosome biogenesis inhibition represents a potential treatment strategy for TERT-reactivated cancers.Highlights➢TERT accelerated thyroid cancer dedifferentiation and metastasisin vivo➢TERT regulated rRNA metabolism and MTORC1/ S6K/RPS6 activities➢CX-5461 inhibited the progression of TERT-reactivated melanoma and thyroid cancer➢Inhibition of rRNA induced redifferentiation of advanced thyroid cancer with TERT activation