Department of Surgery.
Program in Cellular and Molecular Biology.
JCI Insight. 2018 Jan 25;3(2). doi: 10.1172/jci.insight.97422.
Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies.
胰腺癌的特征是几乎普遍存在 KRAS 的激活突变。在其他体细胞突变中，TP53 在超过 75%的人类胰腺肿瘤中发生突变。基因工程小鼠在研究单个基因对致癌作用的贡献方面已被证明是非常有用的工具。致癌性 Kras 突变在胰腺癌变早期发生，被认为是起始事件。相比之下，p53 突变在肿瘤进展过程中发生得较晚。在我们的模型中，我们重现了人类疾病的突变顺序，即致癌性 Kras 表达后发生 p53 突变。此外，我们使用了一种可诱导和可逆表达的突变型 p53 等位基因，在不同的癌变阶段使它失活。值得注意的是，突变型 p53 的功能在癌变的不同阶段发生变化。我们的工作确立了突变型 p53 对于胰腺癌前体病变的形成和维持的必要性。在肿瘤中，突变型 p53 对于生长不再是必需的。然而，它维持了胰腺癌的特征性代谢改变，并介导了其恶性潜能。此外，突变型 p53 促进上皮-间充质转化 (EMT) 和癌细胞侵袭。这项工作产生了新的模拟人类胰腺癌的小鼠模型，并扩展了我们对 p53 突变的作用的理解，p53 突变在大多数人类恶性肿瘤中都很常见。
