Pre-existing cell subpopulations in primary prostate cancer tumors display surface fingerprints of docetaxel-resistant cells.

IF 6.6 2区医学 Q1 Medicine

Cellular Oncology Pub Date : 2024-08-20 DOI:10.1007/s13402-024-00982-2

Stanislav Drápela, Barbora Kvokačková, Eva Slabáková, Anna Kotrbová, Kristína Gömöryová, Radek Fedr, Daniela Kurfürstová, Martin Eliáš, Vladimír Študent, Frederika Lenčéšová, Ganji Sri Ranjani, Vendula Pospíchalová, Vítězslav Bryja, Wytske M van Weerden, Martin Puhr, Zoran Culig, Jan Bouchal, Karel Souček

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引用次数: 0

Abstract

Purpose: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies.

Methods: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint.

Results: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes.

Conclusion: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.

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原发性前列腺癌肿瘤中预先存在的细胞亚群显示出多西他赛耐药细胞的表面指纹。

目的：多西他赛耐药性是治疗前列腺癌（PCa）的一大障碍，导致患者预后不良。瘤内异质性通常与上皮细胞向间质转化（EMT）有关，以前曾被认为是一种有利于适应各种刺激的现象，从而促进了癌细胞的多样性，最终导致对包括多西他赛在内的化疗产生耐药性。因此，了解瘤内异质性对于改善患者预后和制定个性化治疗策略至关重要：为了解决这个问题，我们采用了一种高通量单细胞流式细胞仪方法来识别与多西他赛耐药性相关的PCa细胞特异性表面指纹，并辅以细胞外囊泡的蛋白质组学分析。我们利用体内多西他赛耐药患者衍生异种移植物进一步验证了所选抗原，并对原发性PCa标本进行了探查，以研究其表面指纹：我们的方法揭示了与原发性 PCa 标本中多西他赛耐药相关的 6 个分子表面指纹。我们在体外和体内多西他赛耐药模型中观察到了CD95（FAS/APO-1）和SSEA-4表面抗原的一致过表达，在表现出EMT特征的原发性PCa肿瘤细胞亚群中也观察到了这一现象。此外，在接受多西他赛治疗的 PCa 患者中，CD95 以及参与 SSEA-4 合成的重要酶 ST3GAL1 和 ST3GAL2 的数量显著增加，这与患者的不良生存预后有关：总之，我们证明了在多西他赛治疗前，与多西他赛耐药相关的6分子表面指纹已存在于原发性PCa肿瘤亚群中。因此，这一指纹值得进一步验证，它有望在开始治疗前成为预测 PCa 患者多西他赛耐药性的工具。

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 Biochemistry, Genetics and Molecular Biology-Cancer Research

CiteScore

10.40

自引率

1.50%

发文量

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.