Reconstituting human pancreatic cancer development for translational research

重建人类胰腺癌的发展以进行转化研究

• 批准号: 9217005
• 负责人: Seung K Kim
• 金额: $ 51.56万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217005
• 关键词: 3-Dimensional; Address; Alpha Cell; Archives; Basic Science; Biological Markers; Biological Models; CDKN2A gene; CRISPR/Cas technology; Cell Line; Cells; Characteristics; Chemoprevention; Clinical; Clone Cells; Desmoplastic; Development; Diagnosis; Ductal Epithelial Cell; Ensure; Epithelial; Excision; Generations; Genes; Genetic; Goals; Growth; Human; Immunohistochemistry; Induced Mutation; Intervention; Intervention Studies; KRAS2 gene; Lesion; MADH4 gene; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Methods; Modeling; Modification; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pancreatitis; Pathologic; Prevention; Protein Analysis; Reporting; Research Personnel; Response Latencies; Signal Transduction; Specimen; System; TP53 gene; Testing; Therapeutic Studies; Translational Research; Transplantation; Validation; actionable mutation; anticancer research; base; biomarker discovery; candidate marker; developmental genetics; diagnostic biomarker; effective therapy; molecular marker; novel; oncology; pre-clinical; preclinical development; preclinical study; reconstitution; response; transcriptome sequencing; translational study

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.”

项目总结/摘要 胰腺导管腺癌（PDA）几乎普遍致命，反映了其典型的晚期 诊断，当有效的治疗选择有限。胰腺上皮内瘤变（PanIN） 代表胰腺导管腺癌（PDA）的早期局部发育阶段， 治愈性手术切除仍然可行。了解PDA前驱病变的特征， PanIN可以为早期PDA诊断和干预提供新的策略。我们创建了一个 用于遗传修饰和原代人胰腺细胞生长以重建人胰腺细胞的新系统 具有人PanIN的分子和病理学特征的病变的发展。原位时 移植这些永生化的克隆产生稳定的人诱导的胰腺上皮内 肿瘤（hiPanIN）。此外，这些PanIN病变似乎是稳定的：6个月后， 局部侵袭或转移。在这里，我们建议验证和优化这个新的系统， 稳定的人PanIN样病变，以增强其用于解决未满足的翻译需求的用途。目标1 我们建议产生新的hiPanIN克隆，其突变谱与在天然的hiPanIN中发现的突变谱相匹配。 PanIN和PDA开发。我们还将评估hiPanIN系统中识别的优先生物标志物 在天然人PanIN和PDA标本中。在目标2中，我们提出了合作研究，以测试是否 胰腺炎、进一步的基因修饰或与PDA相关的外在信号可以促进侵袭性或 hiPanIN原位移植模型中的转移性PDA。总之，我们的建议是高度 响应FOA（PAR 16-059）。我们创造了一个“新颖的模式，以填补翻译的关键空白， 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“确保它们适合于解决未满足的翻译需求”。