Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Mol Cancer Res. 2023 Nov 1;21(11):1163-1175. doi: 10.1158/1541-7786.MCR-23-0144.
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.
端粒酶逆转录酶（TERT）基因启动子的突变是一种非编码区域跨癌改变的范例。TERT 启动子突变（TPM）是癌症预后不良的生物标志物，包括甲状腺肿瘤。TPM 增强了 TERT 的转录，而 TERT 在成人组织中是沉默的，从而重新激活了真正的癌蛋白。为了研究 TERT 的失调及其下游后果，我们通过 CRISPR/Cas9 工程对小鼠等效基因座（Tert-123C>T）进行了 Tert 突变启动子小鼠模型的构建，并将其与甲状腺特异性 BrafV600E 突变小鼠进行了杂交。我们还采用了 Tert 过表达的替代模型（K5-Tert）。虽然所有 BrafV600E 动物都发展为分化良好的甲状腺乳头状瘤，但分别有 29%和 36%的 BrafV600E+Tert-123C>T 和 BrafV600E+K5-Tert 小鼠在 20 周时进展为低分化癌。Tert 上调的肿瘤在实体生长区域显示出增加的有丝分裂和坏死，而老年动物表现出类似于间变性的特征，即纺锤形细胞和巨噬细胞浸润。鼠 TPM 在体外和体内均增加了 Tert 的转录，但观察到时间和肿瘤内异质性。甲状腺肿瘤细胞的 RNA 测序显示，除了经典的 Tert 介导的端粒维持作用之外，其他过程也在这些标本中起作用。通路分析显示，MAPK 和 PI3K/AKT 信号通路，以及以前与这种肿瘤病因无关的过程，涉及细胞因子和趋化因子信号通路，被过度激活。这些模型构成了有用的临床前工具，可以了解 Tert 介导的高级甲状腺癌和其他携带 TPM 的侵袭性肿瘤进展中的细胞自主和微环境相关后果。
端粒酶驱动的癌症进展激活了可以被剖析并可能被治疗性利用的途径。
