Telomerase Upregulation induces progression of mouse Braf(V600E)-driven thyroid cancers and triggers nontelomeric effects Journal Article
| Authors: | Landa, I.; Thornton, C. E. M.; Xu, B.; Haase, J.; Krishnamoorthy, G. P.; Hao, J. Z.; Knauf, J. A.; Herbert, Z. T.; Martinez, P.; Blasco, M. A.; Ghossein, R.; Fagin, J. A. |
| Article Title: | Telomerase Upregulation induces progression of mouse Braf(V600E)-driven thyroid cancers and triggers nontelomeric effects |
| Abstract: | Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the paradigm of a cross-cancer alteration in a noncoding region. TERT promoter mutations (TPM) are biomarkers of poor prognosis in cancer, including thyroid tumors. 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>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>T) and Braf(V600E)+K5-Tert mice progressed to poorly differentiated cancers at week 20, respectively. Tert-upregulated tumors showed increased mitosis and necrosis in areas of solid growth, and older animals displayed anaplastic-like features, that is, spindle cells and macrophage infiltration. Murine TPM increased Tert transcription in vitro and in vivo, but temporal and intratumoral 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. These models constitute useful preclinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs. |
| Keywords: | gene; inflammation; in-vitro; expression; nf-kappa-b; subunit; genome-wide analysis; catalytic; tert promoter mutations; braf v600e; major indicator |
| Journal Title: | Molecular Cancer Research |
| Volume: | 21 |
| Issue: | 11 |
| ISSN: | 1541-7786 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-11-01 |
| Start Page: | 1163 |
| End Page: | 1175 |
| Language: | English |
| ACCESSION: | WOS:001112010100005 |
| DOI: | 10.1158/1541-7786.Mcr-23-0144 |
| PROVIDER: | wos |
| PUBMED: | 37478162 |
| PMCID: | PMC11193891 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Wos |
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