高危/局部晚期前列腺癌的腔内干细胞促进对激素治疗的抵抗

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-30 eCollection Date: 2025-01-01 DOI:10.7150/thno.112496
Guyu Tang, Jing Liu, Xiaomei Gao, Kai Yuan, Minfeng Chen, Long Wang, Lin Qi, Yi Cai
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引用次数: 0

摘要

高危/局部晚期前列腺癌(HRLPC)在中国前列腺癌病例中占很大比例,且复发率高。基于雄激素剥夺疗法的治疗提供有限的益处,这可能与治疗后上皮细胞和肿瘤微环境(TME)的变化有关。然而,激素治疗后HRLPC亚群的细胞组成和分子特征尚不清楚。方法:为探讨激素治疗后HRLPC患者残留肿瘤样本的分子特征及复发率高的原因,本研究对9例HRLPC患者进行了单细胞测序。此外,通过建立患者源性类器官(PDOs)并进行药物筛选,我们分析了不同治疗阶段的上皮细胞亚群,并探索了潜在的治疗策略。结果:本研究鉴定了一群具有高SOX9转录活性的管腔干样上皮细胞(Lum stem-like)。激素治疗后,这些细胞仍然存活,并成为上皮腔细胞的主要组成部分。此外,激素治疗后,TME中成纤维细胞和内皮细胞等基质成分的比例显著增加,成纤维细胞与其他细胞之间的细胞间通讯增强。免疫浸润水平下降,但FOXP3+ Treg细胞比例增加,导致免疫微环境处于“耗竭”状态。我们证实PDOs可以准确反映原发肿瘤的上皮亚型,如Lum干细胞样细胞。在类器官水平对18种潜在治疗药物进行药物筛选,结果表明,Lum干细胞样细胞对铂类药物表现出更大的敏感性。结论:本研究确定了HRLPC中占优势的Lum茎样上皮细胞亚群,以及激素治疗后TME的变化,其特征是基质增加和免疫浸润减少。这些发现有助于指导HRLPC患者的后续治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Luminal Stem-like Cells in High-Risk/Locally Advanced Prostate Cancer Promote Resistance to Hormonal Therapy.

Introduction: High-risk/locally advanced prostate cancer (HRLPC) accounts for a large proportion of prostate cancer cases in China and is associated with a high recurrence rate. Androgen deprivation therapy-based treatment offers limited benefits, which may be associated with changes in epithelial cells and the tumor microenvironment (TME) after treatment. However, the cellular composition and molecular characteristics of the subpopulations following hormonal treatment in HRLPC remain unclear. Methods: To investigate the molecular characteristics of residual tumor samples in HRLPC patients following hormonal therapy and to identify the reasons for their high recurrence rates, this study performed single-cell sequencing on nine HRLPC patients. Additionally, by establishing patient-derived organoids (PDOs) and conducting drug screening, we analyzed epithelial cell subpopulations at different treatment stages and explored potential therapeutic strategies. Results: This study identified a population of luminal stem-like epithelial cells (Lum stem-like) with high transcriptional activity of SOX9. After hormonal therapy, these cells were still alive and became the predominant component of epithelial luminal cells. Additionally, after hormonal therapy, the proportion of stromal components, such as fibroblasts and endothelial cells, significantly increased in the TME, and the intercellular communication between fibroblasts and other cells was enhanced. The level of immune infiltration decreased, but the proportion of FOXP3+ Treg cells increased, leading to an "exhausted" immune microenvironment state. We confirmed that PDOs can accurately reflect the epithelial subtypes of the primary tumor, such as Lum stem-like cells. Using 18 potential therapeutic agents at the organoid level for drug screening, the results showed that the Lum stem-like cells exhibited greater sensitivity to platinum-based drugs. Conclusions: This study identified the dominant Lum stem-like epithelial cell subpopulation, along with changes in the TME characterized by increased stroma and decreased immune infiltration after hormonal therapy in HRLPC. These findings can help guide the subsequent treatment strategies for HRLPC patients.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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