SUMOylation regulates the aggressiveness of breast cancer-associated fibroblasts.

IF 6.6 2区 医学 Q1 Medicine Cellular Oncology Pub Date : 2024-10-21 DOI:10.1007/s13402-024-01005-w
Angelica Martínez-López, Guiomar Infante, Marina Mendiburu-Eliçabe, Andrés Machuca, Olga M Antón, Mónica González-Fernández, José L Luque-García, Robert B Clarke, Sonia Castillo-Lluva
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Abstract

Background: Cancer-associated fibroblasts (CAFs) are the most abundant stromal cellular component in the tumor microenvironment (TME). CAFs contribute to tumorigenesis and have been proposed as targets for anticancer therapies. Similarly, dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to tumorigenesis and drug resistance in various cancers, including breast cancer. We explored the role of SUMOylation in breast CAFs and evaluated its potential as a therapeutic strategy in breast cancer.

Methods: We used pharmacological and genetic approaches to analyse the functional crosstalk between breast tumor cells and CAFs. We treated breast CAFs with the SUMO1 inhibitor ginkgolic acid (GA) at two different concentrations and conditioned media was used to analyse the proliferation, migration, and invasion of breast cancer cells from different molecular subtypes. Additionally, we performed quantitative proteomics (SILAC) to study the differential signalling pathways expressed in CAFs treated with low or high concentrations of GA. We confirmed these results both in vitro and in vivo. Moreover, we used samples from metastatic breast cancer patients to evaluate the use of GA as a therapeutic strategy.

Results: Inhibition of SUMOylation with ginkgolic acid (GA) induces death in breast cancer cells but does not affect the viability of CAFs, indicating that CAFs are resistant to this therapy. While CAF viability is unaffected, CAF-conditioned media (CM) is altered by GA, impacting tumor cell behaviour in different ways depending on the overall degree to which SUMO1-SUMOylated proteins are dysregulated. Breast cancer cell lines exhibited a concentration-dependent response to conditioned media (CM) from CAFs. At a low concentration of GA (10 µM), there was an increase in proliferation, migration and invasion of breast cancer cells. However, at a higher concentration of GA (30 µM), these processes were inhibited. Similarly, analysis of tumor development revealed that at 10 µM of GA, the tumors were heavier and there was a greater degree of metastasis compared to the tumors treated with the higher concentration of GA (30 µM). Moreover, some of these effects could be explained by an alteration in the activity of the GTPase Rac1 and the activation of the AKT signalling pathway. The results obtained using SILAC suggest that different concentrations of GA affected cellular processes differentially, possibly influencing the secretome of CAFs. Treatment of metastatic breast cancer with GA demonstrated the use of SUMOylation inhibition as an alternative therapeutic strategy.

Conclusion: The study highlights the importance of SUMOylation in the tumor microenvironment, specifically in cancer-associated fibroblasts (CAFs). Targeting SUMOylation in CAFs affects their signalling pathways and secretome in a concentration-dependent manner, regulating the protumorigenic properties of CAFs.

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SUMOylation 调节乳腺癌相关成纤维细胞的侵袭性。
背景:癌症相关成纤维细胞(CAFs)是肿瘤微环境(TME)中最丰富的基质细胞成分。CAFs 有助于肿瘤发生,并被认为是抗癌疗法的靶点。同样,SUMO机制成分的失调会破坏SUMO酰化的平衡,导致包括乳腺癌在内的多种癌症的肿瘤发生和耐药性。我们探讨了 SUMOylation 在乳腺癌 CAFs 中的作用,并评估了其作为乳腺癌治疗策略的潜力:方法:我们采用药理学和遗传学方法分析了乳腺肿瘤细胞和CAFs之间的功能性串扰。我们用两种不同浓度的SUMO1抑制剂银杏酸(GA)处理乳腺CAFs,并用条件培养基分析不同分子亚型乳腺癌细胞的增殖、迁移和侵袭。此外,我们还进行了定量蛋白质组学(SILAC)研究,以了解经低浓度或高浓度 GA 处理的 CAF 所表达的不同信号通路。我们在体外和体内都证实了这些结果。此外,我们还利用转移性乳腺癌患者的样本来评估将 GA 用作治疗策略的效果:结果:用银杏酸(GA)抑制SUMO酰化可诱导乳腺癌细胞死亡,但不会影响CAFs的活力,这表明CAFs对这种疗法有抵抗力。虽然CAF的活力不受影响,但GA会改变CAF的条件培养基(CM),并根据SUMO1-SUMOylated蛋白失调的总体程度以不同的方式影响肿瘤细胞的行为。乳腺癌细胞系对来自CAFs的条件培养基(CM)表现出浓度依赖性反应。在低浓度 GA(10 µM)条件下,乳腺癌细胞的增殖、迁移和侵袭均有所增加。然而,在较高浓度的 GA(30 µM)下,这些过程受到抑制。同样,对肿瘤发展的分析表明,与使用较高浓度 GA(30 µM)处理的肿瘤相比,使用 10 µM GA 处理的肿瘤更重,转移程度更高。此外,其中一些影响可以通过改变 GTPase Rac1 的活性和激活 AKT 信号通路来解释。使用 SILAC 获得的结果表明,不同浓度的 GA 对细胞过程的影响不同,可能会影响 CAFs 的分泌组。用GA治疗转移性乳腺癌表明,SUMO酰化抑制可作为一种替代治疗策略:该研究强调了 SUMOylation 在肿瘤微环境中的重要性,特别是在癌症相关成纤维细胞(CAFs)中的重要性。靶向 CAFs 中的 SUMOylation 会以浓度依赖的方式影响其信号通路和分泌组,从而调节 CAFs 的原发肿瘤特性。
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
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
期刊最新文献
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