Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-10-05 DOI:10.1016/j.bbadis.2024.167521

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引用次数: 0

Abstract

Background

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive.

Methods

The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated.

Results

Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top ‘hit’ inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations.

Conclusions

IGF-1R plays a critical role in maintaining iCCA-stem like cell populations.

General significance

Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.

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激酶库筛选确定 IGF-1R 是肝内胆管癌干样细胞的致癌弱点。

背景：肝内胆管癌（iCCA）是一种侵袭性极强的外周胆管癌，其特征是肿瘤组织中存在大量癌症干样细胞（CSC）。虽然 iCCA 中的 CSC 标记已明确定义，但这一亚群的分子弱点仍然难以捉摸：方法：96孔三维（3D）瘤球培养是从一个成熟的CSC模型改良而来，通过基因表达分析验证了CSC标记物。然后进行激酶库筛选，以揭示潜在的致癌脆弱通路。利用RNA干扰在三个iCCA细胞系中稳定沉默候选基因，并评估其对iCCA细胞增殖和瘤球形成效率（TFE）的影响：结果：激酶抑制剂库筛选出了对肿瘤球活力至关重要的前50种激酶抑制剂，其中11种抑制剂靶向IGF-1R/PI3K/AKT轴。对 "热门 "抑制剂的进一步剂量依赖性分析证实了IGF-1R是候选分子。稳定沉默IGF-1R后，所有三种iCCA细胞系都表现出AKT活化减少、增殖受阻和TFE降低，表明CSC亚群减少：结论：IGF-1R 在维持 iCCA 干样细胞群中发挥着关键作用：我们的数据强调了 IGF-1R 作为 iCCA 预后标志物和消除其 CSC 亚群治疗靶点的潜在作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.