Analysis of the Plasticity of Circulating Tumor Cells Reveals Differentially Regulated Kinases During the Suspension-to-Adherent Transition

IF 2.9 2区医学 Q2 ONCOLOGY Cancer Medicine Pub Date : 2024-10-18 DOI:10.1002/cam4.70339

Daniel J. Smit, Konstantin Hoffer, Bettina Bettin, Malte Kriegs, Laure Cayrefourcq, Udo Schumacher, Klaus Pantel, Catherine Alix-Panabières, Manfred Jücker

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Abstract

Background

Research on circulating tumor cells (CTCs) offers the opportunity to better understand the initial steps of blood-borne metastasis as main cause of cancer-related deaths. Here, we have used the colon cancer CTC-MCC-41 and breast cancer CTC-ITB-01 lines, which were both established from human CTCs as permanent cell lines as models to further study CTC biology with special emphasis on anchorage-independent survival and growth.

Methods and Results

Both cell lines showed a marked intrinsic plasticity to switch between suspension and adherent in vitro growth, in 2D adherent culture conditions, and established an equilibrium of both growth patterns with predominant adherent cells in the CTC-MCC-41 line (77%) and suspension cells in the CTC-ITB-01 line (85%). Western blot analysis revealed a higher expression of pERK1/2 in CTC-ITB-01 adherent cells compared to the suspension counterpart that suggested the involvement of kinases in this process. Subsequent functional kinome profiling identified several serine/threonine as well as tyrosine kinases that were differentially regulated in adherent and suspension CTCs. In the adherent cells of the breast cancer line CTC-ITB-01 the activity of MSK1, Src family kinases and the PKG family was increased compared to the suspension counterpart. In adherent cells of the colorectal CTC-MCC-41 line, an increased activity of TYRO3 and JAK2 was detected, whereas p38 MAPK was strongly impaired in the suspension CTC-MCC-41 cells. Some of the regulated kinases, which include the Src family, TYRO3, MSK1, JAK2 and p38 MAPK, have been associated with crucial cellular processes including proliferation, migration and dormancy in the past.

Conclusions

The investigated CTC lines exhibit a high plasticity, similar to the concept of ‘adherent-to-suspension transition (AST)’ that was recently suggested as a new hallmark of tumor biology by Huh et al. Moreover, we identified differentially regulated kinome profiles that may represent potential targets for future studies on therapeutic interventions.

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循环肿瘤细胞的可塑性分析揭示了从悬浮到粘附转变过程中的不同调控激酶

背景：循环肿瘤细胞（CTCs）是导致癌症相关死亡的主要原因，对循环肿瘤细胞（CTCs）的研究为更好地了解血行转移的初始步骤提供了机会。在此，我们以结肠癌 CTC-MCC-41 和乳腺癌 CTC-ITB-01 细胞系为模型，进一步研究 CTC 的生物学特性，特别强调锚定依赖性生存和生长：在二维粘附培养条件下，两种细胞系都显示出明显的内在可塑性，可在体外悬浮生长和粘附生长之间切换，并建立了两种生长模式的平衡，CTC-MCC-41系中粘附细胞占优势（77%），CTC-ITB-01系中悬浮细胞占优势（85%）。Western 印迹分析显示，与悬浮细胞相比，CTC-ITB-01 吸附细胞中 pERK1/2 的表达量更高，这表明激酶参与了这一过程。随后进行的功能激酶组分析发现，在粘附和悬浮的 CTC 中，几种丝氨酸/苏氨酸和酪氨酸激酶受到不同程度的调控。在乳腺癌品系 CTC-ITB-01 的粘附细胞中，MSK1、Src 家族激酶和 PKG 家族的活性都比悬浮细胞高。在结直肠癌 CTC-MCC-41 株系的粘附细胞中，检测到 TYRO3 和 JAK2 的活性增加，而悬浮的 CTC-MCC-41 细胞中 p38 MAPK 的活性严重受损。一些受调控的激酶，包括 Src 家族、TYRO3、MSK1、JAK2 和 p38 MAPK，过去一直与增殖、迁移和休眠等关键细胞过程有关：研究发现的 CTC 株系表现出高度的可塑性，与 Huh 等人最近提出的作为肿瘤生物学新标志的 "粘附到悬浮转变（AST）"概念相似。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.