Reconstituting human pancreatic cancer development for translational research

项目摘要/摘要 摘要胰腺导管腺癌(Pda)是一种常见的致命性肿瘤，表现为典型的晚期胰腺癌。 诊断，当有效的治疗选择有限时。胰腺上皮内瘤变(Panins) 代表胰腺导管腺癌(PDA)的早期、局限性发展阶段，当 根治性手术切除仍然是可行的。了解PDA前驱病变的特点，如 Panins可以为PDA的早期诊断和干预创造新的策略。我们已经创建了一个 一种新的原代人胰腺细胞基因修饰和生长系统 具有人类Panins分子和病理特征的病变的发展。关于正位的 移植这些永生化克隆产生稳定的人诱导的胰腺上皮内细胞 肿瘤(HiPanINs)。此外，这些Panin病变似乎是稳定的：6个月后，它们不再稳定 局部侵袭或转移。在这里，我们建议验证和优化这一新系统，以生成 稳定的人类Panin样病变，以增强其在解决未满足的翻译需求方面的用途。在目标1中 我们建议生成新的hiPanIN克隆，其突变谱与在自然环境中发现的一致 Panin和PDA的发展。我们还将评估在hiPanIN系统中确定的优先生物标记物 在土生土长的人类Panin和PDA标本中。在目标2中，我们建议进行协作研究，以测试 胰腺炎、进一步的基因修饰或与PDA相关的外部信号可以促进侵袭性或 HiPanIN原位移植模型中的转移性动脉导管未闭总而言之，我们的建议是高度的 对FOA作出回应(标准杆16-059)。我们创造了一种新的模式来填补翻译领域的关键空白 要求“使用”人类和哺乳动物肿瘤学模型及其遗传学“，以及拟议的研究 以“确保它们在满足未得到满足的翻译需求方面的适当性。”

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDA) is almost universally lethal, reflecting its typical late-stage diagnosis, when effective treatment options are limited. Pancreatic intra-epithelial neoplasias (PanINs) represent an early, localized developmental stage of pancreatic ductal adenocarcinoma (PDA), when curative surgical resection remains feasible. Understanding features of PDA precursor lesions like PanINs could generate new strategies for early PDA diagnosis and intervention. We have created a novel system for genetic modification and growth of primary human pancreatic cells to reconstitute the development of lesions with molecular and pathological features of human PanINs. Upon orthotopic transplantation these immortalized clones produce stable human induced pancreatic intra-epithelial neoplasias (hiPanINs). Moreover, these PanIN lesions appear to be stable: after 6 months, they do not invade locally or metastasize. Here we propose to validate and optimize this new system for generating stable human PanIN-like lesions to enhance its uses for addressing unmet translational needs. In Aim 1 we propose to generate new hiPanIN clones whose mutational spectrum matches that found in native PanIN and PDA development. We will also assess prioritized biomarkers identified in the hiPanIN system in native human PanIN and PDA specimens. In Aim 2 we propose collaborative studies to test whether pancreatitis, further genetic modification, or extrinsic signals relevant to PDA can promote invasive or metastatic PDA in the hiPanIN orthotopic transplantation model. In summary our proposal is highly responsive to the FOA (PAR 16-059). We have created a “novel model to fill critical gaps in translational requirements” using “human and mammalian oncology models and their genetics”, and proposed studies to “ensure their appropriateness for addressing unmet translational needs.”