American Association for Cancer Research
mcr-23-0144_supplementary_figure_4_suppsf4.pdf (366.51 kB)

Supplementary Figure 4 from Telomerase Upregulation Induces Progression of Mouse BrafV600E-Driven Thyroid Cancers and Triggers Nontelomeric Effects

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journal contribution
posted on 2023-08-02, 14:20 authored by Iñigo Landa, Caitlin E.M. Thornton, Bin Xu, Jacob Haase, Gnana P. Krishnamoorthy, Jingzhu Hao, Jeffrey A. Knauf, Zachary T. Herbert, Paula Martínez, María A. Blasco, Ronald Ghossein, James A. Fagin

Additional analyses of RNA sequencing data from mouse tumors with telomerase upregulation.



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 BrafV600E-mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all BrafV600E animals developed well-differentiated papillary thyroid tumors, 29% and 36% of BrafV600E+Tert−123C>T and BrafV600E+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. Telomerase-driven cancer progression activates pathways that can be dissected and perhaps therapeutically exploited.

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