Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma

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. This study consists of 12 RNA-seq samples. These samples were isolated from subcutaneous tumors of KCip53-1 cells grown in NSG mice. Tumor treatment consisted of three groups: animals treated with dox for the entire course of the experiment (Dox), animals never treated with dox (No Dox), and animals who began the experiment on dox and then had it removed (Off Dox). In the KCip53-1 mouse pancreatic cancer cell line, dox induces the expression of mutant p53R270H.

胰腺癌以KRAS几乎普遍存在的激活性突变为核心特征。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（genetically engineered mice）已被证实为研究单个基因对致癌作用贡献的关键实验模型。致癌性Kras突变在胰腺癌发生进程中较早出现，被认为是肿瘤起始事件。与之相反，p53突变多发生于肿瘤进展阶段。
本研究构建的模型重现了人类胰腺癌的突变发生时序，即致癌性Kras表达之后才出现p53突变。此外，我们利用可诱导且可逆的突变型p53表达等位基因，在致癌进程的不同阶段使其表达失活。值得关注的是，突变型p53的功能会随致癌进程的不同阶段发生动态改变。本研究证实，突变型p53对于胰腺癌前病变的形成与维持是必需的。在实体肿瘤中，突变型p53对于肿瘤生长不再必需，但可维持胰腺癌特有的代谢改变，并介导肿瘤的恶性潜能。此外，突变型p53可促进上皮间质转化（epithelial-mesenchymal transition, EMT）与癌细胞侵袭。
本研究成功构建了可模拟人类胰腺癌的新型小鼠模型，深化了我们对p53突变（该突变在多数人类恶性肿瘤中均较为常见）作用机制的理解。
本研究共包含12个RNA测序（RNA-seq）样本，上述样本分离自接种于NSG小鼠体内的KCip53-1细胞所形成的皮下肿瘤。肿瘤处理分为三组：全程接受多西环素（dox）处理的实验组（Dox组）、全程未接受多西环素处理的对照组（No Dox组），以及先接受多西环素处理后停药的实验组（Off Dox组）。
在KCip53-1小鼠胰腺癌细胞系中，多西环素可诱导突变型p53R270H的表达。