{"doi":"10.1101/2023.01.24.525280","title":"Telomerase reactivation induces progression of mouse Braf <sup>V600E</sup> -driven thyroid cancers without telomere lengthening","abstract":"ABSTRACT Mutations in the promoter of the telomerase reverse transcriptase ( TERT ) gene are the paradigm of a cross-cancer alteration in a non-coding region. TERT promoter mutations (TPMs) are biomarkers of poor prognosis in several tumors, including thyroid cancers. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert -123C&gt;T ) and crossed it with thyroid-specific Braf V600E -mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all Braf V600E animals developed well-differentiated papillary thyroid tumors, 29% and 36% of Braf V600E +Tert -123C&gt;T and Braf V600E +K5-Tert mice progressed to poorly differentiated thyroid cancers at week 20, respectively. Braf+Tert tumors showed increased mitosis and necrosis in areas of solid growth, and older animals from these cohorts displayed anaplastic-like features, i.e., spindle cells and macrophage infiltration. Murine Tert promoter mutation increased Tert transcription in vitro and in vivo , but temporal and intra-tumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine and chemokine signaling, were overactivated. Braf+Tert animals remained responsive to MAPK pathway inhibitors. These models constitute useful pre-clinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398258,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1063554,"name":"Caitlin E.M. Thornton","orcid":"0000-0003-1787-1155","position":1,"is_corresponding":false},{"id":250488,"name":"Bin Xu","orcid":"0000-0003-4638-9835","position":2,"is_corresponding":false},{"id":1046488,"name":"Jacob Haase","orcid":"0000-0003-0960-6546","position":3,"is_corresponding":false},{"id":277158,"name":"Gnana P. Krishnamoorthy","orcid":"0000-0002-6139-5435","position":4,"is_corresponding":false},{"id":1063555,"name":"Jingzhu Hao","orcid":"0009-0005-0386-9080","position":5,"is_corresponding":false},{"id":277160,"name":"Jeffrey A. Knauf","orcid":"0000-0003-4456-8792","position":6,"is_corresponding":false},{"id":1403,"name":"Zachary T. Herbert","orcid":"0000-0001-9401-2464","position":7,"is_corresponding":false},{"id":36442,"name":"Marı́a A. Blasco","orcid":"0000-0002-4211-233X","position":8,"is_corresponding":false},{"id":13486,"name":"Ronald Ghossein","orcid":"0000-0003-2802-8489","position":9,"is_corresponding":false},{"id":108810,"name":"James A. Fagin","orcid":"0000-0002-2365-2517","position":10,"is_corresponding":false},{"id":657320,"name":"Iñigo Landa","orcid":"0000-0002-2817-8295","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T01:19:43.776284Z","pmid":"36747657","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}