Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
Oncogene. 2020 Jul;39(30):5282-5291. doi: 10.1038/s41388-020-1358-5. Epub 2020 Jun 19.
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics of ACC has hampered progress in the field. We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/β-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized the Cyp11b2(AS) mouse line to generate mice with adrenocortical-specific Wnt/β-catenin activation, Trp53 deletion, or the combination of both. Mice with targeted Wnt/β-catenin activation or Trp53 deletion showed no changes associated with tumor formation. In contrast, alterations in both pathways led to ACC with pulmonary metastases. Similar to ACCs in humans, these tumors produced increased levels of corticosterone and aldosterone and showed a high proliferation index. Gene expression analysis revealed that mouse tumors exhibited downregulation of Star and Cyp11b1 and upregulation of Ezh2, similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/β-catenin and p53/Rb signaling is sufficient to drive ACC in mouse. This autochthonous model of ACC represents a new tool to investigate the biology of ACC and to identify new treatment strategies.
肾上腺皮质癌（ACC）是一种罕见且侵袭性强的恶性肿瘤，治疗选择有限。缺乏能够重现 ACC 遗传学的小鼠模型，阻碍了该领域的进展。我们分析了癌症基因组图谱（TCGA）数据库中的 ACC 数据，发现同时存在 p53/Rb 和 Wnt/β-catenin 信号通路改变的患者比仅存在一种改变的患者预后更差。为了模拟这种情况，我们利用 Cyp11b2(AS) 小鼠系产生了肾上腺皮质特异性 Wnt/β-catenin 激活、Trp53 缺失或两者组合的小鼠。靶向 Wnt/β-catenin 激活或 Trp53 缺失的小鼠没有与肿瘤形成相关的变化。相比之下，两条通路的改变导致了具有肺转移的 ACC。与人类的 ACC 相似，这些肿瘤产生了增加的皮质酮和醛固酮水平，并显示出高增殖指数。基因表达分析显示，与预后不良的 ACC 患者一样，小鼠肿瘤表现出 Star 和 Cyp11b1 的下调和 Ezh2 的上调。总的来说，这些数据表明改变 Wnt/β-catenin 和 p53/Rb 信号足以在小鼠中驱动 ACC 的发生。这种原发性 ACC 模型代表了一种新的工具，可以研究 ACC 的生物学并确定新的治疗策略。
