Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells.
Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells.
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DOI：
10.1038/ncomms14686
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发表时间：
2017-03-08
影响因子：
16.6
通讯作者：
Kim SK
中科院分区：
文献类型：
--
作者：
Lee J;Snyder ER;Liu Y;Gu X;Wang J;Flowers BM;Kim YJ;Park S;Szot GL;Hruban RH;Longacre TA;Kim SK
重建人类胰腺上皮内瘤变（PanIN）（胰腺导管腺癌的前身）标志性特征的系统的开发可以产生早期诊断和干预的新策略。然而，具有明确突变的基于人类细胞的 PanIN 模型尚不可用。在这里，我们报告原代人胰腺细胞的基因修饰导致类似于天然人 PanIN 的病变的发展。含有致癌 KRAS 和 CDKN2A、SMAD4 和 TP53 诱导突变的原代人胰腺导管细胞在体外以上皮球形式扩展。胰腺移植后，突变克隆形成组织学上与天然 PanIN 相似的病变，包括显着的基质反应。基因表达谱揭示了突变克隆与天然 PanIN 的分子相似性，并鉴定了潜在的 PanIN 生物标志物候选物，包括 Neuromedin U（一种循环肽激素）。原代细胞对人类 PanIN 发育的前瞻性重建为研究胰腺癌的发生、进展和早期检测提供了实验机会。人类胰腺上皮内瘤变 (PanIN) 发展模型尚不存在。在这里，作者在原代人胰腺细胞中诱导致癌 KRAS 以及 CDKN2A、SMAD4 和 TP53 突变，以生成 PanIN 模型，该模型概括了天然 PanIN 的分子和病理特征。
Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring oncogenic KRAS and induced mutations in CDKN2A, SMAD4 and TP53 expand in vitro as epithelial spheres. After pancreatic transplantation, mutant clones form lesions histologically similar to native PanINs, including prominent stromal responses. Gene expression profiling reveals molecular similarities of mutant clones with native PanINs, and identifies potential PanIN biomarker candidates including Neuromedin U, a circulating peptide hormone. Prospective reconstitution of human PanIN development from primary cells provides experimental opportunities to investigate pancreas cancer development, progression and early-stage detection. Models of human pancreatic intraepithelial neoplasia (PanIN) development do not exist. Here, the authors induce oncogenic KRAS and mutations in CDKN2A, SMAD4 and TP53 in primary human pancreatic cells to generate a PanIN model that recapitulates molecular and pathologic features of native PanINs.