ABSTRACT Pancreatic cancer constitutes a genetic disease in which somatic mutations in the KRAS proto-oncogene are detected in 95% of cases. Activation of the KRAS proto-oncogene represents an initiating event in pancreatic tumorigenesis. Here, we established a zebrafish pancreatic neoplasia model that recapitulates human pancreatic tumors. Toward this end, we generated a stable CRE/Lox-based zebrafish model system to express oncogenic KRASG12D in the elastase3I domain of the zebrafish pancreas. Lineage tracing experiments showed that early KRASG12D -responsive pancreatic progenitors contribute to endocrine in addition to exocrine cells. In this system, 10% and 40% of zebrafish developed pancreatic tumors by 6 and 12 months, respectively. The histological profiles of these experimental tumors bore a striking resemblance to those of pancreatic endocrine tumors. Immunohistochemical analysis including the endocrine cell-specific marker confirmed the pancreatic tumor region as a characteristic endocrine tumor. Taken together, our zebrafish model data revealed that pancreatic endocrine tumors originate from early KRASG12D -responsive pancreatic progenitor cells. These findings demonstrated that this zebrafish model may be suitable as an experimental and preclinical system to evaluate different strategies for targeting pancreatic endocrine tumors and ultimately improve the outcome for patients with pancreatic endocrine tumors.

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KRAS 引发的胰腺内分泌肿瘤的斑马鱼模型

摘要 胰腺癌是一种遗传性疾病，其中 95% 的病例中检测到 KRAS 原癌基因的体细胞突变。KRAS 原癌基因的激活代表了胰腺肿瘤发生的起始事件。在这里，我们建立了一个重现人类胰腺肿瘤的斑马鱼胰腺肿瘤模型。为此，我们生成了一个稳定的基于 CRE/Lox 的斑马鱼模型系统，以在斑马鱼胰腺的弹性蛋白酶3I 域中表达致癌 KRASG12D。谱系追踪实验表明，早期 KRASG12D 反应性胰腺祖细胞除外分泌细胞外还有助于内分泌。在该系统中，分别有 10% 和 40% 的斑马鱼在 6 个月和 12 个月时出现了胰腺肿瘤。这些实验性肿瘤的组织学特征与胰腺内分泌肿瘤的组织学特征非常相似。包括内分泌细胞特异性标记物在内的免疫组织化学分析证实胰腺肿瘤区域为特征性内分泌肿瘤。总之，我们的斑马鱼模型数据显示胰腺内分泌肿瘤起源于早期对 KRASG12D 有反应的胰腺祖细胞。这些发现表明，这种斑马鱼模型可能适合作为实验和临床前系统来评估针对胰腺内分泌肿瘤的不同策略，并最终改善胰腺内分泌肿瘤患者的预后。总之，我们的斑马鱼模型数据显示胰腺内分泌肿瘤起源于早期对 KRASG12D 有反应的胰腺祖细胞。这些发现表明，这种斑马鱼模型可能适合作为实验和临床前系统来评估针对胰腺内分泌肿瘤的不同策略，并最终改善胰腺内分泌肿瘤患者的预后。总之，我们的斑马鱼模型数据显示胰腺内分泌肿瘤起源于早期对 KRASG12D 有反应的胰腺祖细胞。这些发现表明，这种斑马鱼模型可能适合作为实验和临床前系统来评估针对胰腺内分泌肿瘤的不同策略，并最终改善胰腺内分泌肿瘤患者的预后。