Introduction: Five year survival of pancreatic cancer (PC) remains low. Current murine models may not adequately mimic human PC and can be too small for medical device development. A large animal PC model could address these issues. We induced and characterized pancreatic tumors in Oncopigs (transgenic swine with a somatic floxed cassette containing KRASG12D and TP53R167H). Methods: Oncopigs underwent injection of adenovirus expressing Cre recombinase (AdCre) +/- interleukin 8 (IL-8) into one of the main pancreatic ducts (induction procedure). Subjects were necropsied after <10 week, followed by histological analysis, cytokine expression analysis, exome sequencing and transcriptome analysis of resultant tumors. Results: Fourteen Oncopigs underwent the induction procedure; ten (71%) had gross tumor within three weeks, one of these subjects expired suddenly and the other 9 required premature euthanasia secondary to lack of oral intake. At necropsy all of ten of these subjects had gastric outlet obstruction secondary to pancreatic tumor and phlegmon. Two Oncopigs underwent a control injection (no AdCre) and four WT littermates of the Oncopigs underwent AdCre injection without notable effect. Exome and transcriptome analysis of the porcine pancreatic tumors revealed similarity with the molecular signatures and pathways of human PC. Conclusion: Oncopigs with ductal injection of AdCre developed pancreatic tumor in a short period of time with molecular characteristics similar to human PC. While further optimization and validation of this porcine PC model would be beneficial, it is anticipated that this model will be useful for focused research and development of diagnostic and therapeutic technologies for PC.

中文翻译：

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在 KRAS/TP53 Oncopig 中诱导胰腺肿瘤

简介：胰腺癌 (PC) 的五年生存率仍然很低。当前的小鼠模型可能无法充分模拟人类 PC，并且对于医疗设备开发而言可能太小。大型动物 PC 模型可以解决这些问题。我们在 Oncopigs（具有含有 KRASG12D 和 TP53R167H 的体细胞 floxed 盒的转基因猪）中诱导并表征了胰腺肿瘤。方法： Oncopigs 将表达 Cre 重组酶 (AdCre) +/- 白细胞介素 8 (IL-8) 的腺病毒注射到主胰管之一（诱导程序）。<10 周后对受试者进行尸检，然后对所得肿瘤进行组织学分析、细胞因子表达分析、外显子组测序和转录组分析。结果：14 只 Oncopig 接受了诱导程序；十人（71%）在三周内出现肉眼瘤，其中一名受试者突然死亡，另外 9 名受试者因缺乏口服摄入而需要过早安乐死。在尸检时，所有这些受试者中的 10 人都有继发于胰腺肿瘤和痰液的胃出口梗阻。两只 Oncopigs 接受了对照注射（无 AdCre），四只 On​​copigs 的 WT 同窝仔接受了 AdCre 注射，但没有显着效果。猪胰腺肿瘤的外显子组和转录组分析显示与人类 PC 的分子特征和通路相似。结论：导管注射AdCre的Oncopigs在短时间内发展为胰腺肿瘤，其分子特征与人类PC相似。虽然这种猪 PC 模型的进一步优化和验证将是有益的，