间质细胞在胆管癌中的作用。

IF 4 3区 医学 Q2 CELL BIOLOGY Disease Models & Mechanisms Pub Date : 2024-11-04 DOI:10.1242/dmm.050716
Mireia Sueca-Comes, Elena Cristina Rusu, Jennifer C Ashworth, Pamela Collier, Catherine Probert, Alison Ritchie, Marian Meakin, Nigel P Mongan, Isioma U Egbuniwe, Jesper Bøje Andersen, David O Bates, Anna M Grabowska
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引用次数: 0

摘要

肿瘤微环境(TME)通过动态的相互作用对肿瘤的形成和发展产生重要影响。胆管癌(CCA)是一种高度脱鳞的肿瘤,由于对其分子发病机制了解不全面,因此缺乏早期诊断生物标志物,有效的治疗方法也很有限。研究TME在CCA进展过程中的作用可以找到更好的治疗方法。研究人员对 7 个 CCA PDX 及其相应的患者样本进行了 RNA 测序。进行了差异表达分析,并使用Qiagen Ingenuity Pathway Analysis(IPA)预测了失调通路和上游调控因子。对含有或不含有永生化间充质干细胞的PDX和细胞系衍生球形体进行了培养,并对其形态、生长和存活率进行了分析。组织学分析证实了胆汁表型。RNA测序表明,间充质干细胞存在时,ECM-受体相互作用和PI3K-Akt通路上调,其中几个基因与存活率低有关。间充质干细胞恢复了被抑制的癌症相关激酶(ICAKs)的活性。这项研究表明,在CCA球状模型中加入间充质干细胞可恢复PDXs中丧失的关键旁分泌信号通路,从而增强肿瘤的生长和存活能力。这些发现强调了在癌症模型中加入基质成分以改善临床前研究的重要性。
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The role of mesenchymal cells in cholangiocarcinoma.

The tumour microenvironment (TME) significantly influences tumour formation and progression through dynamic interactions. Cholangiocarcinoma (CCA), a highly desmoplastic tumour, lacks early diagnostic biomarkers and has limited effective treatments due to an incomplete understanding of its molecular pathogenesis. Investigating the TME's role in CCA progression could lead to better therapies. RNA sequencing was performed on seven CCA PDXs and their corresponding patient samples. Differential expression analysis was conducted, and Qiagen Ingenuity Pathway Analysis (IPA) was used to predict dysregulated pathways and upstream regulators. PDX and cell line-derived spheroids, with and without immortalised mesenchymal stem cells, were grown and analysed for morphology, growth, and viability. Histological analysis confirmed biliary phenotypes. RNA sequencing indicated upregulation of ECM-receptor interaction and PI3K-Akt pathways in the presence of MSCs, with several genes linked to poor survival. MSCs restored the activity of inhibited cancer-associated kinases (ICAKs). This study shows that adding MSCs to CCA spheroid models restores key paracrine signalling pathways lost in PDXs, enhancing tumour growth and viability. These findings highlight the importance of including stromal components in cancer models to improve pre-clinical studies.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
期刊最新文献
A frameshift mutation in the murine Prkra gene exhibits cerebellar abnormality and reduced eIF2α phosphorylation. Slc26a2-mediated sulfate metabolism is significant for the tooth development. Modelling quiescence exit of neural stem cells reveals a FOXG1-FoxO6 axis. The role of mesenchymal cells in cholangiocarcinoma. Hippo cooperates with p53 to regulate lung airway mucous cell metaplasia.
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