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Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.
Cell Stem Cell ( IF 23.9 ) Pub Date : 2018-Mar-01 , DOI: 10.1016/j.stem.2017.12.009
Takashi Seino , Shintaro Kawasaki , Mariko Shimokawa , Hiroki Tamagawa , Kohta Toshimitsu , Masayuki Fujii , Yuki Ohta , Mami Matano , Kosaku Nanki , Kenta Kawasaki , Sirirat Takahashi , Shinya Sugimoto , Eisuke Iwasaki , Junichi Takagi , Takao Itoi , Minoru Kitago , Yuko Kitagawa , Takanori Kanai , Toshiro Sato

Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression.

中文翻译:

人胰腺肿瘤类器官显示疾病进展过程中干细胞生态位因子依赖性的丧失。

尽管最近通过确定特定亚型的预后预测基因表达特征来剖析胰腺导管腺癌(PDAC)的肿瘤间异质性,但它们的功能差异仍然难以捉摸。在这里,我们建立了一个胰腺肿瘤类器官库,该库包含39个患者来源的PDAC,并基于它们对Wnt和R-spondin的干细胞利基因子依赖性,确定了3种功能亚型。不产生Wnt的亚型需要癌相关的成纤维细胞产生Wnt,而在不存在Wnt和R-spondin的情况下,产生Wnt的亚型可自主分泌Wnt配体和不依赖R-spondin的亚型。对PDAC类器官的转录组分析揭示了基因表达特征,这些特征将Wnt小众亚型与GATA6依赖性基因表达亚型相关联,这在功能上受到GATA6遗传干扰的支持。此外,基于CRISPR-Cas9的PDAC驱动基因(KRAS,CDKN2A,SMAD4和TP53)的基因组编辑证明了胰腺肿瘤发生过程中Wnt生态位独立性的非遗传获取。总的来说,我们的研究结果揭示了PDAC中Wnt小生境独立性的功能异质性是通过肿瘤进展非遗传形成的。
更新日期:2018-01-11
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