An engineered pancreatic cancer model with intra-tumoral heterogeneity of driver mutations.,Lab on a Chip

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An engineered pancreatic cancer model with intra-tumoral heterogeneity of driver mutations.
Lab on a Chip ( IF 6.1 ) Pub Date : 2020-09-02 , DOI: 10.1039/d0lc00707b
Hye-Ran Moon ₁ , Altug Ozcelikkale , Yi Yang , Bennett D Elzey , Stephen F Konieczny , Bumsoo Han

Affiliation

Pancreatic ductal adenocarcinoma (PDAC) is a complex disease with significant intra-tumoral heterogeneity (ITH). Currently, no reliable PDAC tumor model is available that can present ITH profiles in a controlled manner. We develop an in vitro microfluidic tumor model mimicking the heterogeneous accumulation of key driver mutations of human PDAC using cancer cells derived from genetically engineered mouse models. These murine pancreatic cancer cell lines have KPC (Kras and Trp53 mutations) and KIC genotypes (Kras mutation and Cdkn2a deletion). Also, the KIC genotypes have two distinct phenotypes – mesenchymal or epithelial. The tumor model mimics the ITH of human PDAC to study the effects of ITH on the gemcitabine response. The results show gemcitabine resistance induced by ITH. Remarkably, it shows that cancer cell–cell interactions induce the gemcitabine resistance potentially through epithelial–mesenchymal-transition. The tumor model can provide a useful testbed to study interaction mechanisms between heterogeneous cancer cell subpopulations.

中文翻译：

具有驱动突变肿瘤内异质性的工程胰腺癌模型。

胰腺导管腺癌（PDAC）是一种复杂的疾病，具有显着的瘤内异质性（ITH）。目前，还没有可靠的 PDAC 肿瘤模型能够以受控方式呈现 ITH 谱。我们使用源自基因工程小鼠模型的癌细胞开发了一种体外微流体肿瘤模型，模拟人类 PDAC 关键驱动突变的异质积累。这些小鼠胰腺癌细胞系具有 KPC（Kras和Trp53突变）和 KIC 基因型（Kras突变和Cdkn2a缺失）。此外，KIC 基因型有两种不同的表型——间质型或上皮型。该肿瘤模型模拟人 PDAC 的 ITH，以研究 ITH 对吉西他滨反应的影响。结果显示ITH诱导吉西他滨耐药。值得注意的是，它表明癌细胞与细胞的相互作用可能通过上皮-间质转化诱导吉西他滨耐药。肿瘤模型可以提供有用的测试平台来研究异质癌细胞亚群之间的相互作用机制。

更新日期：2020-10-13

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